Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens. Implications for hepatitis B e antigen seroconversion.

T cell proliferative responses to hepatitis B virus-encoded envelope antigen (S + preS2 + preS1), recombinant core antigen (HBcAg), and natural hepatitis B e antigen (HBeAg) were examined in 22 HBeAg-positive patients with chronic type B hepatitis and 17 healthy hepatitis B surface antigen (HBsAg) carriers. The results showed that HBeAg-positive patients had (a) higher levels of T cell responses to HBcAg/HBeAg than those of healthy HBsAg carriers (P less than 0.001 and P less than 0.01, respectively); (b) a further increase in these T cell responses during acute exacerbations (P less than 0.05 and P less than 0.05, respectively); (c) subsidence in the T cell responses to HBcAg/HBeAg after recovery from acute exacerbations and HBeAg seroconversion, whereas the responses would persist at high levels if the patients did not enter a clinical remission; and (d) low levels of T cell responses to S + preS2 + preS1 either before or after HBeAg seroconversion. The appearance of increasing T cell responses to HBcAg/HBeAg usually occurred in the early phase of acute exacerbations. These findings imply that HBcAg/HBeAg-specific T cells play an important role in the exacerbations of chronic hepatitis B and in HBeAg seroconversion. HBcAg/HBeAg-specific precursor T cell frequencies were serially studied in selected cases by limiting dilution assay. Elevation (two- to fourfold) of HBcAg/HBeAg-specific precursor T cell frequencies contributed to the increase of HBcAg/HBeAg-specific T cell proliferation during acute exacerbations.

Changes in ploidy distributions in human liver carcinogenesis.

Cellular and nuclear DNA content was measured by flow cytometry and the fraction of binucleated cells by fluorescence microscopy in normal adult human livers, hepatocellular carcinomas, cirrhotic livers surrounding tumors, and in some benign liver conditions. In five normal livers about one-half of the hepatocytes were polyploid; the majority of these were binucleated tetraploids containing two diploid nuclei. Thus, polyploidization in human liver does not progress as far as, for example, in the rat, where 80%-90% of adult hepatocytes are polyploid, mostly with tetraploid or octoploid nuclei. In five human euploid hepatocellular carcinomas and one investigated case of focal nodular hyperplasia, the percentage of polyploid cells was significantly reduced. Four other carcinomas exhibited a prominent aneuploid (hypotetraploid) peak in addition to the diploid peak. An abnormally low fraction of binucleated cells was also indicated in these tumors. Liver tissue surrounding the tumors had a ploidy distribution similar to that of normal liver. The results suggest that, like in several models of experimental hepatocarcinogenesis, human hepatocellular tumor growth is associated with a decreased polyploidization tendency and a corresponding increase in diploid, divisional growth, which may give the tumors a growth advantage relative to the surrounding liver.

Low-power laserthermia for the treatment of small hepatocellular carcinoma.

Laserthermia by a novel interstitial probe adapted to low power Nd-YAG laser machine was used to treat small hepatocellular carcinoma (HCC). The set condition was 43-45 degrees C in thermocouple with power of 2-3 W and the duration 20-30 min. In the 5 cases studied, 1 had a good result with total necrosis of the tumour without recurrence in 16 months. 1 died of liver failure 2.5 months later although death was not related to the procedure. 1 patient died of progressive disease 18 months later. The remaining 2 had recurrent tumours 5 and 12 months later, although the treated small tumours showed good response. Histological examination showed cell degeneration and necrosis. It is concluded that laserthermia is potentially useful in the treatment of the patients with small HCC.

Local radiotherapy with or without transcatheter arterial chemoembolization for patients with unresectable hepatocellular carcinoma.

PURPOSE: To evaluate the treatment outcome, patterns of failure, and prognostic factors for patients with unresectable hepatocellular carcinoma (HCC) treated with local radiotherapy alone or as an adjunct to transcatheter arterial chemoembolization (TACE). METHODS AND MATERIALS: From March 1994 to December 1997, 25 patients with unresectable HCC underwent local radiotherapy to a portion of the liver. Twenty-three patients were classified as having cirrhosis in Child-Pugh class A and 2 in class B. Mean diameter of the treated hepatic tumor was 10.3 cm. Mean dose of radiation was 46.9 +/- 5.9 Gy in a daily fraction of 1.8-2 Gy. Sixteen patients were also treated with Lipiodol and chemotherapeutic agents mixed with Ivalon or Gelfoam particles for chemoembolization, either before and/or after radiotherapy. Percutaneous ethanol injection therapy (PEIT) was given to one patient. All patients were monitored for treatment-related toxicity and for survival and patterns of failure. RESULTS: In a median follow-up period of 23 months, 11 patients were alive and 14 dead. The median survival duration from treatment was 19.2 months with a 2-year survival of 41%. Only 3 of 25 patients had local progression of the treated hepatic tumor. The recurrences were seen within the liver or extrahepatic. The 2-year local, regional, and extrahepatic progression-free survival rates were 78%, 46%, and 39%, respectively. The local control ranked the highest. Patients with Okuda Stage I disease had significantly longer survival than those with Stage II and III (p = 0.02). Patients with T4 disease (p = 0.02) or treated with radiotherapy alone (p = 0.003) had significantly shorter survival. T4 disease (p = 0.03) and pretreatment alpha-fetoprotein level of more than 200 ng/ml (p = 0. 03) were associated with significantly worse regional progression-free survival. A significant difference was observed in both regional progression-free survival (p = 0.0001) and extrahepatic progression-free survival (p = 0.005) between patients with and without portal vein thrombosis before treatment. The presence of satellite nodules had a significantly worse impact on regional progression-free survival (p = 0.04) and extrahepatic progression-free survival (p = 0.03). Patients with hepatic tumor more than 6 cm in diameter or portal vein thrombosis tended to have shorter survival. Radiation-induced liver disease (RILD) and gastrointestinal bleeding were the most common treatment-related toxicities. CONCLUSION: Radiotherapy is effective in the treatment of patients with unresectable HCC. Its effect appeared to be more prominent within the site to which radiation was given. The combination of TACE and radiation was associated with better control of HCC than radiation given alone, probably due to the selection of patients with favorable prognosis for the combined treatment. A dose-volume model should be established in the next phase of research in the treatment of unresectable HCC.

The protective efficacy of recombinant hepatitis B vaccine in newborn infants of hepatitis B e antigen-positive-hepatitis B surface antigen carrier mothers.

Recombinant hepatitis B vaccine has been shown to be as safe and effective as plasma-derived vaccines. However, its efficacy in the prevention of perinatal infection has not been fully evaluated in an endemic area. We recruited 110 high risk infants born to hepatitis B e antigen-positive-hepatitis B surface antigen (HBsAg) carrier mothers in a study of recombinant vaccine efficacy. They were randomized into 2 groups, A (54 infants) and B (56 infants), to receive 4 doses of vaccine, containing 20 or 10 micrograms of surface antigen, respectively, at 0, 1, 2 and 12 months of age. An additional 60 high risk infants were recruited later (Group C) and received three 20-micrograms doses of vaccine at 0, 1 and 6 months of age. All infants also received a dose (145 IU) of hepatitis B immunoglobulin soon after birth. Sera were collected at 0, 1, 2, 3, 6, 12 and 14 months of age to assay HBsAg and anti-HBs. At 12 months of age the HBsAg carrier rates were 7.4 and 1.8%, in Groups A and B, respectively. In Group C the HBsAg-positive rate was 3.3%. HBsAg was invariably first observed between 0 and 2 months of age. Virtually all noncarrier infants developed substantial titers of anti-HBs at 12 months of age. No serious adverse effect was observed after vaccination.

Characterization of T Cell Clones Specific to a Determinant of Hepatitis B Virus Core and e Antigens in Chronic Type B Hepatitis: Implication for a T Cell Mechanism of HBV Immunopathogenesis.

T cell clones specific for hepatitis B core (HBcAg) and e (HBeAg) antigens of hepatitis B virus (HBV) were generated from liver infiltrates of HBeAg-positive patients. Analyzed with a panel of overlapping synthetic peptides spanning the complete sequences of HBcAg and HBeAg, eight clones responded specifically to the e2 peptide (PAYRPPNAPIL; amino acid residues 130-140 of HBcAg and HBeAg), which was doubly restricted by class I and II molecules. A preferential usage of the T cell receptor (TCR) alpha chain variable (V(alpha)) gene was found: V(alpha)12.1 for five HLA-Cw9(3)-restricted cytotoxic T lymphocyte (CTL) clones, and V(alpha)7.1 for three other HLA-DRw52-restricted type 1 helper T cell (Th1) clones. Although heterogeneous in the usage of TCR alpha chain joining region (J(alpha)) segments, their junctional-region sequences revealed conserved hydrophilic serine residues in seven of the eight e2-specific T cell clones. Single alanine substitution of the centrally located and the only hydrophilic asparagine residue of e2 peptide abrogated T cell responsiveness. The nonstimulatory e2 analogue could competitively inhibit e2-specific responses. These results demonstrate that both CTL and Th1 clones recognizing a determinant of HBcAg and HBeAg are present in the liver of chronic hepatitis B patients. The preferential V(alpha) gene usage and the expression of conserved residues in junctional-region sequences of TCRalpha chains by viral-peptide-specific, intrahepatic T cells may provide a T cell mechanism of HBV immunopathogenesis. Copyright 1994 S. Karger AG, Basel

Intraoperative hepatic ultrasonography--an indispensable procedure in resection of small hepatocellular carcinomas.

Hepatic ultrasonography (US) was performed during laparotomy in 47 patients with hepatocellular carcinomas (HCC) less than 5 cm in size. It detected more tumors than did preoperative US and other imaging modalities. In this series, 45.9% of HCCs smaller than 3 cm and 14.2% of those between 3 and 5 cm were invisible and impalpable during laparotomy, and another 15.5% of the total of HCCs were only partially visible or equivocally palpable; thus they needed intraoperative US to make a three-dimensional localization of the tumors. We concluded that, in the resection of small HCCs, intraoperative US should serve as a routine procedure.

Surgical treatment of 109 patients with symptomatic and asymptomatic hepatocellular carcinoma.

A total of 109 patients with histologically proved hepatocellular carcinoma (HCC) have undergone hepatic resection during the 56-month period from October 1978 to May 1983. There were two sources of patients: those with symptomatic HCC (n = 47) and those with asymptomatic HCC (n = 62). A family tendency of HCC was noted in 11% of the patients studied. The percent of positive hepatitis B surface antigen (HBsAg) was 87%, and the serum alpha-fetoprotein was less than 20 ng/ml in 30% in the group with symptoms. The operative mortality rate was 3% and the hospital mortality rate was also 3%. The postoperative course was complicated with pleural effusion in 10%, bile leakage in 4%, subphrenic abscess in 4%, and upper gastrointestinal bleeding caused by gastritis in 1% of the patients. The actual survival rate for the 103 cases was 84% for 350 days and 28% for 1400 days. However, in the group with asymptomatic HCC with an average tumor size of 3.35 +/- 1.49 cm in diameter, the rate was 92% for 350 days and 44% for 1400 days. In the group with symptomatic HCC with an average tumor size of 10.6 +/- 5.1 cm in diameter, the rate was 76% for 350 days and 8% for 1400 days. The survival rate of the group with asymptomatic HCC was far better than that of the group with symptoms (p less than 0.05). In analysis of factors that might affect the patient's survival, only second or third operations (p less than 0.05), typical gross findings of tumor appearance (p less than 0.05), and an adequate margin were closely related (p less than 0.001). Neither the tumor size, the status of accompanying liver cirrhosis, the tumor location, nor the patient's sex and age affected the patient's survival (all p greater than 0.05).

Noninvasive diagnosis of advanced pancreatic cancer by real-time ultrasonography, carcinoembryonic antigen, and carbohydrate antigen 19-9.

One-hundred-forty patients with clinical impression of pancreatic cancer were examined prospectively with three noninvasive tests: real-time ultrasonography, determination of serum carcinoembryonic antigen (CEA), and carbohydrate antigen (CA 19-9). Among them, 24 (17.1%) patients were found to have pancreatic cancer. The sensitivity of ultrasonography, CEA, and CA 19-9 was 72.9%, 70.8%, and 83.3%, respectively; the specificity was 94.0%, 77.6%, and 90.5%, respectively, and the diagnostic accuracy was 91.4%, 76.4%, and 89.3%, respectively. The combination of ultrasonography and determination of serum CA 19-9 had better sensitivity (95.8%), comparable specificity (84.5%), and comparable diagnostic accuracy (86.4%) to any individual test alone or any other combination. It was suggested that combined use of real-time ultrasonography and determination of serum CA 19-9 provided excellent noninvasive screening for patients suspected of having pancreatic cancer.

Pancreatic carcinoma associated with chronic calcifying pancreatitis in Taiwan: a case report and review of the literature.

A 62-year-old Chinese woman suffering from pancreatic carcinoma coexisting with chronic calcifying pancreatitis is reported. Ultrasonography and computed tomography disclosed multiple intraductal calcifications in the pancreatic head and body and a tumor at the tail. Laparotomy revealed cancerous peritonitis in addition to verifying the presence of calcifications at the head and body and a cancer at the tail. Histology confirmed adenocarcinoma. The incidence of pancreatic carcinoma in chronic calcifying pancreatitis varied from 0.8 to 25% in a thorough review of the literature. It is emphasized that patients with chronic calcifying pancreatitis should be closely followed for detection of possible coexisting pancreatic malignancies.

HLA-A, B, C and DR antigens in chronic hepatitis B viral infection.

To study the role of genetic factors in hepatitis B virus (HBV)-related liver diseases, HLA typing with 47 specificities of HLA-A, B, C and DR loci using Terasaki's 2-stage microlymphocytotoxicity method was performed in 253 normal subjects and 305 patients with various HBV-related liver diseases, including 95 healthy carries of HBV, 30 with chronic persistent hepatitis (CPH), 74 with chronic active hepatitis (CAH), 51 with liver cirrhosis and 55 with hepatocellular carcinoma (HCC). The frequency of HLA-B17 was significantly higher in patients with HCC than in healthy carriers (27.3% vs 4.2%, Pc less than 0.01). A similar situation was noted for HLA-DR3 in a comparison of patients with CAH and healthy carriers (37% vs 10%, Pc less than 0.05). Comparisons among various groups involving other specificities were statistically nonsignificant. It is concluded that genetic predisposition to the development of CAH, as well as HCC is present in HBsAg carriers, and further clarification of underlying mechanisms is needed.

Hepatitis Be antigen and antibody in chronic liver diseases and hepatocellular carcinoma.

The presence of hepatitis Be antigen (HBeAg) and antibody (anti-HBe) was investigated by immunodiffusion in 144 patients with chronic liver disease, and 129 with hepatocellular carcinoma (HCC). Most of the patients were HBsAg-positive. In 62 patients with chronic active viral hepatitis B, 17 (27%) were positive for HBeAg and 25 (40%) for anti-HBe. HBeAg and anti-HBe were not related to the degree of histological activity or serum alanine aminotransferase activities, but were related more frequently to higher HBsAg titer and younger age; whereas anti-HBe generally correlated in an opposite manner. Two patients seroconverted from HBeAg to anti-HBe in 13 and 20 months respectively. HBs antigenemia was not eliminated in either HBeAg or anti-HBe positive patients. The prolonged interval in seroconversion and an age-related declining frequency of HBeAg, accompanied by a reciprocal increase in anti-HBe in chronic infection, suggest anti-HBe as a chronologic indicator in HBs antigenemia in chronic HBsAg carriage. In HCC, regardless of coexisting cirrhosis, a predominant frequency of anti-HBe (62%) was found as in cirrhosis (54%), suggesting longstanding HBsAg carriage in these patients.

Reactivation of hepatitis B virus in anti-HBe-positive chronic active type B hepatitis: molecular and immunohistochemical studies.

The causes of acute clinical exacerbations, and the role of reactivation of hepatitis B virus (HBV) in 16 non-cirrhotic patients with chronic active type B hepatitis (CAH-B) negative for serum hepatitis B e antigen (HBeAg) but positive for anti-HBE, were studied by molecular hybridization and immunohistochemical methods. IgM antibody to hepatitis A virus (anti-HAV IgM) and antibody to delta agent (anti-delta) were negative in all. HBeAg reappeared transiently in only two patients. Serum hepatitis B virus (HBV) DNA levels increased during acute exacerbations in 14 patients (88%), and decreased after the episode. Cytoplasmic hepatitis B core antigen (HBcAg) expression was found in 9 out of 13 patients (69%) during acute exacerbation. By Southern blot hybridization, 5 of 6 (83%) liver tissues obtained during clinical exacerbations had free replicative forms of HBV DNA. In 20 control patients with no exacerbation, serum HBV DNA, HBcAg expression in hepatocytes and free replicative forms of HBV DNA were positive in 15% (3/20), 10% (2/20) and 25% (2/8), respectively--figures significantly lower than those of the group studied. We conclude that acute exacerbations sometimes seen in patients with anti-HBe-positive CAH-B in Taiwan are caused mainly by reactivation of HBV.

Intratumor injection of OK-432 for the treatment of small hepatocellular carcinoma.

Intratumor injection of OK-432, a biological response modifier, in the treatment of small HCC was studied in 7 inoperable patients. After evaluation with ultrasound (US), computed tomography (CT), angiography and US-guided biopsy, implantation of a steel coil in the tumor, intratumor injection was performed under US guidance. After completion of the treatment, liver biopsy and image studies were again done to evaluate the extent of tumor necrosis. One patient was alive and well without recurrence 19 months after treatment. Four had recurrent tumors at different site of the liver 4 months, 9 months, 9 months and 8 months later. Two died of progressive malignancy 3 months and 8 months later. In the 6 patients with elevated serum alpha-fetoprotein (AFP) levels, 4 had decreased AFP after treatment, and the 2 mortalities had steadily increased AFP. The most common side effects are fever and chills. Transient abdominal pain with elevated transaminase activities, cough with hemoptysis, and vomiting were seen in 1 case each. After treatment, the biopsy specimens showed total necrosis of HCC. Although the T4/T8 ratio of peripheral blood was increased as compared with that before treatment in 4 cases, peritumoral cytotoxic T lymphocyte and monocyte infiltration were seen in one specimen only, and another 7 examined specimens showed negative staining with monoclonal antibodies of T cells. We conclude that intratumor injection of OK-432 is an alternative treatment for small HCC in inoperable cases. The effectiveness may be due to the direct tumoricidal mechanism of OK-432.

Clinicopathologic studies of asymptomatic HBsAg carriers: with special emphasis on carriers older than 40 years.

To investigate the clinicopathologic features of asymptomatic carriers of hepatitis B surface antigen (HBsAg), liver biopsies were obtained in 140 carriers followed-up for more than 6 months. They included 47 older than 40 years and 75 with elevated SGPT values at least once during the follow-up period. Among the 93 carriers younger than 39 years, milder histologic changes than chronic persistent hepatitis (CPH) were seen in most of those with normal SGPT values, while more severe histologic changes (chronic lobular hepatitis, chronic active hepatitis and active cirrhosis) were found in 18 out of 50 with elevated SGPT values. In contrast, when the carriers were more than 40 years of age, the histologic liver changes became "bipolar", i.e., either very mild or quite severe, since among 47 subjects in this group, 37 (79%) had hepatic lesions milder than CPH, and the remaining 10 (21%) had cirrhosis. The positive rate of hepatitis B e antigen (HBeAg) was not significantly different among those with milder and those with more severe histologic changes in the younger group. However, that of the older carriers was significantly higher among those with liver cirrhosis (50% vs. 16.2%, p less than 0.05). The results imply that, in Taiwan where chronic HBsAg carriage usually occurs in early childhood, a poorer prognosis may exist in asymptomatic HBsAg carriers when HBeAg persists beyond the age of 40.

Intratumor injection of absolute ethanol under ultrasound guidance for the treatment of small hepatocellular carcinoma.

For the treatment of small hepatocellular carcinoma, intratumor injection of absolute ethanol under ultrasound guidance was performed in 27 tumors in 23 patients, with a tumor diameter of between 1.0 and 3.3 cm. The initially elevated serum alpha-fetoprotein levels in 15 patients decreased during treatment, with 13 returning to normal after this regimen. In the 6 patients who finally received surgical resection, 4 had complete necrosis of the tumor, while the other 2 had a small peripheral residual cancer nest. In the remaining non-resected 17 cases, follow-up CT, multiple biopsies and angiography revealed evidence of viable tumor in only 3 cases. After additional ethanol injections, these 3 cases were successfully treated. Inhomogeneous distribution of the injected ethanol and difficulty in identifying the tumor after previous injections accounted for the incomplete necrosis of the tumor. To cope with these problems, a steel coil was implanted in the tumor before treatment, and a needle with multiple side holes was used in the last 3 cases, with satisfactory results. Ethanol injection is promising and may even be curative in the treatment of small hepatocellular carcinoma.

Colonoscopic screening for families of patients with colorectal cancer.

We conducted a prospective study using primary colonoscopy in the families of patients with surgically treated colorectal cancer (CRC) to evaluate its feasibility as a screening method for CRC. The presumed detection sensitivity of sigmoidoscopy in this group was also evaluated. Over a 3-year period, 142 first-degree relatives (73 men and 69 women) of 117 patients with CRC participated in this colonoscopic screening study. The average age at presentation for examination was 49.1 years (range, 31-79 yr). Forty-nine patients had adenomatous polyps (AP) and four patients had cancer, yielding a frequency of 37% (53/142). Thirty-six family members were under 40 years of age, eight of whom had AP. In total, there were 111 AP and four invasive cancers; 42% (48/111) of AP and 75% (3/4) of cancers were beyond the reach of conventional flexible sigmoidoscope. Of 53 patients with AP or cancer in the large bowel, 36 had AP or cancer in the distal colon (rectosigmoid region and descending colon), 15 (42%) of whom were found to have at least one AP or cancer in the proximal colon (proximal to the descending colon). The remaining 17 patients' lesions were confined to the proximal colon, and would not have been detected with a flexible sigmoidoscope. Sigmoidoscopy in high-risk patients with neoplasm in the large bowel has a sensitivity of 68%. We conclude that a vigorous surveillance program using primary colonoscopy should be set up for those who are first-degree relatives of patients with CRC. Routine examination should start at the age of 40, and the entire colon should be evaluated.

Therapeutic effect of ursodeoxycholic acid on early-stage primary biliary cirrhosis.

Primary biliary cirrhosis is a rare chronic liver disease in Taiwan, which eventually causes mortality. As yet, no safe and effective treatment has been found. To investigate the safety and therapeutic efficacy of recently introduced ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis, an uncontrolled trial was conducted in 6 patients in the early stages (I-II) and 5 patients in the late stages (III-IV). Five patients in stage I and one patient in stage II were treated with 10-15 mg/kg/day UDCA for a mean administration period of 13 +/- 9 months. Levels of laboratory tests including serum alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) improved significantly within one month and were sustained at the new lower levels for the period of observation. The symptoms of one patient with pruritus were reduced after long-term therapy. No major side effects were found during the treatment period. In contrast to early-stage patients, patients with late-stage primary biliary cirrhosis who received UDCA therapy for a mean duration of 25 +/- 5 months showed no beneficial effects either clinically or biochemically. From these preliminary results, UDCA appears to be safe and effective in the treatment of early-stage primary biliary cirrhosis, although further controlled clinical trials in conjunction with histological follow-up are mandatory to evaluate the critical role of UDCA in primary biliary cirrhosis.

Famotidine in the treatment of duodenal ulcers resistant to other histamine H2-receptor antagonists.

In 20% of patients with duodenal ulcers, treatment is ineffective. Ulcers are considered resistant when they fail to heal following 8-12 weeks of treatment with full dose duodenal ulcer therapy. The present study reviewed the records and endoscopic findings of 73 patients who were considered by their physicians to have resistant duodenal ulcers. From this population, 15 patients with documented, active duodenal ulcers were chosen to participate in this study. Each had failed treatment with cimetidine or ranitidine at recommended doses administered for from 56 days to more than 2 years. After up to 6 weeks' treatment with 20 mg famotidine given twice daily, eight patients showed endoscopic evidence of healing (S1 or S2) based on the criteria established by the Japanese Society of Digestive Endoscopy. Five others showed moderate to marked improvement H1-H3). No patient experienced side-effects during famotidine treatment. The greater antisecretory effect of famotidine may be useful in treating duodenal ulcer patients who fail to heal with cimetidine or ranitidine.

Preoperative concurrent chemotherapy and radiotherapy in rectal cancer patients.

The management of rectal cancer has changed significantly in recent years. The key end-point is no longer survival but rather preservation of sphincter function with improved quality of life. Preoperative radiation can not only render a low-lying rectal tumor amenable to sphincter-preserving surgery but has also been reported to give better local control and lower toxicity than postoperative radiotherapy. From October 1991 through July 1996, 46 patients with local advanced or low-lying rectal cancer were treated with preoperative high-dose radiotherapy and concurrent chemotherapy. All patients underwent pelvic radiotherapy with 5,000 to 5,400 cGy in 25 to 27 fractions. Chemotherapy was given concomitantly and consisted of two courses of 5-fluorouracil (5-FU) at 1,000 mg/m2 for 4 days in week 1 and week 5 plus mitomycin C 10 mg/m2 single bolus on day 1 of week 1. In 30 patients, postoperative adjuvant chemotherapy with 5-FU and levamisole weekly was also given, for a total of 12 months. The most common acute toxicity was grade 1 to 2 diarrhea and tenesmus during radiation or soon afterward. Only five of the 46 patients experienced symptomatic grade 3 acute toxicity. Forty-two patients underwent subsequent surgery 6 to 8 weeks after concurrent chemoradiotherapy. Pathologic examination disclosed complete tumor regression in eight patients and microscopic residual disease in 13 patients after preoperative chemoradiation. Of the 42 patients who completed the intended treatments, only one had local recurrence. The sphincter was preserved in 21 of the 26 patients in whom the tumor was located within 5 cm above the anal verge. Twelve of the 16 evaluable patients had good to excellent sphincter function. The 2-year overall survival rate was 93% and the disease-free survival was 81%. Our findings indicate that preoperative concurrent chemoradiotherapy not only allows low-lying rectal tumors to be resected while preserving sphincter function but also results in good local control and acceptable toxicity.