Assessment of HER2 gene amplification in adenocarcinomas of the stomach or gastroesophageal junction in the INT-0116/SWOG9008 clinical trial.

BACKGROUND: Trastuzumab has been approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric carcinoma; however, relatively little is known about the role of HER2 in the natural history of this disease. PATIENTS AND METHODS: Patients enrolled in the INT-0116/SWOG9008 phase III gastric cancer clinical trial with available tissue specimens were retrospectively evaluated for HER2 gene amplification by FISH and overexpression by immunohistochemistry (IHC). The original trial was designed to evaluate the benefit of postoperative chemoradiation compared with surgery alone. RESULTS: HER2 gene amplification rate by FISH was 10.9% among 258 patients evaluated. HER2 overexpression rate by IHC was 12.2% among 148 patients evaluated, with 90% agreement between FISH and IHC. There was a significant interaction between HER2 amplification and treatment with respect to both disease-free survival (DFS) (P = 0.020) and overall survival (OS) (P = 0.034). Among patients with HER2-non-amplified cancers, treated patients had a median OS of 44 months compared with 24 months in the surgery-only arm (P = 0.003). Among patients with HER2-amplified cancers, there was no significant difference in survival based on treatment arm. HER2 status was not a prognostic marker among patients who received no postoperative chemoradiation. CONCLUSION: Patients lacking HER2 amplification benefited from treatment as indicated by both DFS and OS. CLINICAL TRIAL: INT-0116/SWOG9008 phase III.

Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors.

PURPOSE: Fluorouracil (5-FU) continuous infusion is superior to 5-FU bolus in patients with advanced colorectal cancer, but the survival difference between the two treatments is small and, therefore, the difference in toxicity profile is crucial in choosing a treatment for individual patients. MATERIALS AND METHODS: We conducted a meta-analysis of all randomized trials that compared 5-FU bolus with 5-FU CI, based on individual data from 1,219 patients, to compare the toxicity of the two schedules of 5-FU administration and to identify predictive factors for toxicity. The toxicities considered were World Health Organization (WHO) grade 3 to 4 anemia, thrombopenia, leukopenia, neutropenia, nausea/vomiting, diarrhea, mucositis, and hand-foot syndrome. RESULTS: Hematologic toxicity, mainly neutropenia, was more frequent with 5-FU bolus than with 5-FU CI (31% and 4%, respectively; P < .0001). Hand-foot syndrome was less frequent with 5-FU bolus than with 5-FU CI (13% and 34%, respectively; P < .0001). There was no difference between the two treatment groups in terms of other nonhematologic toxicities. Independent prognostic factors were age, sex, and performance status for nonhematologic toxicities, performance status, and treatment for hematologic toxicities, and age, sex, and treatment for hand-foot syndrome. CONCLUSION: Based on a large data set, this study confirmed and quantified the toxicity profile of the two schedules of administration of 5-FU and allowed the identification of clinical predictors of toxicity.

Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer.

PURPOSE: The administration of fluorouracil (5-FU) by continuous intravenous infusion (CI) is an alternative to the bolus administration of 5-FU in patients with advanced colorectal cancer. Although more than 1,200 patients have been enrolled onto randomized trials that compared these two treatment modalities, there is still no definitive evidence of an advantage of 5-FU CI, and the magnitude of this advantage, if any, is also controversial. A meta-analysis was performed to assess this benefit in terms of tumor response and survival, and to compare the toxicity profiles of these two modalities of administration of 5-FU. DESIGN: Individual data of 1,219 patients included in six randomized trials served as the basis for this meta-analysis, which was conducted by an independent secretariat in close collaboration with the investigators. RESULTS: Tumor response rate was significantly higher in patients assigned to 5-FU CI than in patients assigned to 5-FU bolus (22% v 14%; overall response odds ratio, 0.55; 95% confidence interval [95% CI], 0.41 to 0.75; P = .0002). Overall survival was also significantly higher in patients assigned to 5-FU CI (overall hazards ratio [HR], 0.88; 95% CI, 0.78 to 0.99; P = .04), although the median survival times were close. Multivariate analyses showed that randomized treatment and performance status were the only two significant predictors of tumor response, whereas the same plus primary tumor site were independent significant predictors of survival (patients with rectal cancer did somewhat better). Grade 3 or 4 hematologic toxicity was more frequent in patients assigned to 5-FU bolus (31% v 4%; P < 10(-16)), whereas hand-foot syndrome was more frequent in the 5-FU CI group (34% v 13%; P < 10(-7)). CONCLUSION: 5-FU CI is superior to 5-FU bolus in terms of tumor response and achieves a slight increase of overall survival. The hematologic toxicity is much less important in patients who receive 5-FU CI, but hand-foot syndrome is frequent in this group of patients.

Acquired immunodeficiency syndrome. Cerebrospinal fluid findings in patients before and during long-term oral zidovudine therapy.

Fifty-two patients with acquired immunodeficiency syndrome were enrolled in this study to evaluate the relationship between cerebrospinal fluid (CSF) zidovudine concentrations and neurologic and human immunodeficiency virus (HIV) culture findings. Paired HIV-CSF culture and neurologic measurements were available in 30 and 45 patients, respectively. Twenty-nine patients were assessable for zidovudine CSF concentrations. Patients underwent lumbar puncture and neurologic testing before and after 8 weeks or more of oral zidovudine therapy (600 to 1500 mg/d). After 8 weeks of therapy, the frequency of HIV isolation from CSF cultures was unchanged. Significant neurologic improvement by examination was noted in 61.5% (32/52) of the patients. The median CSF zidovudine concentration among 29 patients was 0.047 mg/L (range, 0.015 to 0.198 mg/L). No correlation between CSF zidovudine concentration, cumulative dose, or HIV isolation from CSF and persistence or resolution of neurologic symptoms or signs was observed. The mechanisms by which zidovudine improves neurologic function are unclear and appear unrelated to direct clearance of virus from CSF.

Frequency and reactivation of nongenital lesions among patients with genital herpes simplex virus.

OBJECTIVE: To determine the frequency, recurrence patterns, and host factors associated with nongenital herpes simplex virus lesions. PATIENTS AND METHODS: In this cohort study at a referral clinic, 457 patients with first episodes of genital herpes were prospectively observed to evaluate the anatomic sites of herpetic lesions at the first and subsequent visits. Of these patients, 73 had primary genital herpes simplex virus (HSV) type 1, 326 had primary first episode genital HSV-2, and 58 had HSV-1 infection prior to acquisition of genital HSV-2. The median follow-up was 63 weeks. RESULTS: Nongenital lesions at the time of acquisition of genital herpes were observed in 25%, 9%, and 2% of patients with primary HSV-1, primary HSV-2, and nonprimary HSV-2, respectively. Half of the patients with concurrent genital and nongenital lesions subsequently had recurrences at a nongenital site. Twenty patients (6.5%) whose primary genital HSV-2 infection involved only the genitalia subsequently developed nongenital recurrences, primarily on the buttocks (12) and legs (4). Nongenital recurrences, especially buttock recurrences, tended to be less frequent but of longer duration than genital recurrences. CONCLUSIONS: Overall, 21% of patients with primary genital herpes will have or will subsequently develop a nongenital recurrence. Among patients with HSV-1, nongenital lesions tended to occur more often on the hand and face, whereas HSV-2 lesions appeared more often on the buttocks. Buttock lesions due to HSV recur less frequently but last longer than genital lesions.

Double-blind, placebo-controlled trial comparing long-term suppressive with short-term oral acyclovir therapy for management of recurrent genital herpes.

A total of 156 patients with frequently recurring genital herpes were enrolled in a randomized, double-blind, one-year trial comparing long-term suppressive and intermittent oral acyclovir therapy with placebo in the management of recurrent genital herpes. Subjects received either suppressive treatment with acyclovir, 400 mg twice daily for one year, and 200 mg five times per day for five days, for short-term treatment of recurrences; intermittent treatment with placebo, twice daily for one year, and oral acyclovir, 200 mg five times per day for five days, for short-term treatment of recurrences; or treatment with placebo, twice daily for one year, and five times per day for five days for short-term treatment of recurrences. Median time to first recurrence was 250 days for the suppressive group, 28 days for the intermittent group, and 23 days for the placebo group (p = 0.001). The median number of days per month with active disease was 0.32 for the suppressive group, 4.18 for the intermittent group, and 4.72 for the placebo group (p less than 0.001), with a median recurrence rate per 30-day treatment period of 0.08 recurrences/patient in the suppressive group, 0.70 in the intermittent group, and 0.74 in the placebo group (p less than 0.001). Median duration of recurrence was 5.0 days in the suppressive group compared with 6.0 days in the combined intermittent acyclovir plus placebo group (p = 0.001), and was reduced from 7.0 to 6.0 days when intermittent acyclovir treatment was compared with placebo treatment (p = 0.05). Daily administration of oral acyclovir for one year is superior to intermittent or placebo treatment in the management of patients with frequently recurring genital herpes.

Double-blind controlled trial of topical acyclovir in genital herpes simplex virus infections.

Sixty-nine patients with first episodes and 111 with recurrent episodes of genital herpes simplex virus (HSV) infection were enrolled in a double-blind trial comparing a 5 percent topical acyclovir ointment versus placebo, polyethylene glycol (PEG). Among acyclovir recipients with first episodes of genital herpes, the mean duration of viral shedding from genital lesions, 2.0 days, mean duration of local pain or itching, 3.6 days, and mean time to healing of lesions, 11.2 days, were less than in placebo recipients 4.6, 6.7, and 15.8 days, respectively (p less than 0.05 for each comparison). Among patients with recurrent genital herpes, the mean duration of viral shedding from genital lesions was 0.8 days in acyclovir recipients compared with 1.7 days in placebo recipients (p less than 0.001). Among men with recurrent genital herpes, the mean time to crusting and healing of lesions was 3.5 and 7.5 days in acyclovir recipients compared with 5.0 and 9.7 days in placebo recipients, p = 0.03 and 0.07, respectively. No significant differences in the duration of symptoms or healing times were noted between acyclovir- and placebo-treated women with recurrent genital herpes. Acyclovir therapy was not associated with a decrease in frequency of clinical recurrences or an increase in the time of the next recurrence in patients with either first or recurrent genital herpes. Topical acyclovir appears effective in shortening some of the clinical manifestations of genital HSV infections.

A randomized, double-blind, phase I/II trial of tumor necrosis factor and interferon-gamma for treatment of AIDS-related complex (Protocol 025 from the AIDS Clinical Trials Group).

To determine safety and efficacy of tumor necrosis factor (TNF) and interferon-gamma (IFN gamma) in the treatment of patients with acquired immunodeficiency syndrome (AIDS)-related complex, a randomized, double-blind study was conducted. Twenty-five patients with AIDS-related complex and CD4 lymphocytes less than or equal to 500 x 10(6)/L attended an AIDS Clinical Trials Unit of a tertiary referral center. Patients were administered tumor necrosis factor (TNF) (10 micrograms/m2) or IFN gamma (10 micrograms/m2), or both intramuscularly three times weekly for 16 weeks. Side effects from all three preparations included fever, constitutional symptoms, and local reactions. No significant hematologic, hepatic, renal, or coagulation abnormalities were observed. CD4 lymphocyte counts, beta 2-microglobulin, p24 antigen levels, and anti-p24 antibody did not change significantly during therapy. Similarly, no significant change was noted in rates of HIV isolation from peripheral blood mononuclear cells or plasma. TNF and IFN gamma were tolerable after premedication with acetaminophen; however, no significant change in markers of human immunodeficiency virus infection was demonstrated. These cytokines alone do not appear to be of benefit, nor do they appear to hasten the progression of HIV infection.

Asymptomatic maternal shedding of herpes simplex virus at the onset of labor: relationship to preterm labor.

OBJECTIVE: To determine if fetal growth restriction and prematurity are observed with subclinical shedding of herpes simplex virus (HSV) at the onset of labor. METHODS: Within 48 hours of delivery, cultures were taken from the cervix and external genitalia of 15,923 asymptomatic pregnant women without symptoms or signs of genital HSV infection; results were positive for HSV in 57. Each of these 57 women were compared with a control group composed of the three culture-negative women delivering immediately before and the three delivering immediately after each woman shedding HSV. RESULTS: The median birth weight for infants born to the 57 women with asymptomatic shedding was 3050 g, compared with 3360 g among the 342 women without asymptomatic shedding, a statistically significant difference (P < .002). These differences were due to very low birth weight (LBW) among the five infants of women with subclinical viral shedding secondary to recently acquired primary genital herpes; these five infants had a median gestational age of 33 weeks, compared with 37 weeks for the 14 infants of mothers with nonprimary, first-episode disease and 39 weeks for the 33 infants of women with reactivation disease, also a significant difference (P = .018). CONCLUSIONS: Asymptomatic genital shedding of HSV at the onset of labor because of subclinical primary genital HSV infection is associated with preterm delivery. Women who acquire genital HSV-2 before pregnancy and are shedding subclinically at the onset of labor experience no increase in adverse outcome. Thus, prevention of the prematurity and LBW associated with genital herpes means that acquisition of the infection in late pregnancy must be prevented.

Inadequate documentation and resection for gastric cancer in the United States: a preliminary report.

Patients entered into Southwest Oncology Group gastric adjuvant protocol INT 0016 (SWOG 9008) after a "curative" gastric resection were assessed to determine practice patterns of more than 300 surgeons nationwide who performed "curative" gastric resections for 453 gastric cancer patients. The most common gastric resection performed was distal in 256 patients, proximal in 118, and total in 79. Extragastric organs resected were omentum (285), spleen (59), pancreas (18), and bowel (17). The extent of lymphadenectomy as staged by Japanese rules was 246 (54.2%) D0 resections, 173 (38.1%) D1 resections, 28 (6.2%) D2 resections, and 7 (1.5%) D3 resections. Staging of the cancer was poorly documented, with no statement made regarding the status of the primary cancer in 6 per cent, liver in 10 per cent, lymph nodes in 17 per cent, and omentum in 17 per cent. The greater the lymph node clearance, the greater the chance of resecting to a level of negative lymphatics, given that 45 per cent of nodes were involved when 10 or less were removed, whereas only 17 per cent were positive when more than 40 were cleared. The lack of adequate clearance of lymph nodes and poor documentation of tumor stage suggests that a more regimented surgical approach to this uncommon cancer is required.

Levels of cadmium in kidney and liver tissues among a Canadian population (province of Québec).

In an exploratory study, levels of cadmium in whole-kidney and liver tissues of 314 subjects from the general population of the province of Quebec (Canada) were measured postmortem. Frequency distributions of cadmium concentrations were lognormal. As reported in similar studies, age and especially smoking habits were the main variables affecting cadmium concentrations. The geometric mean of whole kidney concentrations (wet weight) was 17.62 microg/g, with a minimum concentration of 2.25 microg/g and a maximum of 100.61 microg/g. Mean concentrations of cadmium in kidneys increased with age, reaching a plateau in the group 50 to 59 yr (29.49 microg/g), and falling slowly thereafter.

Unusually high blood cadmium associated with cigarette smoking among three subgroups of the general population, Quebec, Canada.

Blood cadmium levels were measured in 554 persons without any known professional exposure to this metal. They were grouped in three samples; one entirely of 142 Inuit, one of 212 caucasian city dwellers and one of 200 caucasian rural residents. While blood cadmium levels measured in non-smokers are comparable to those reported in published reports, those of current cigarette smokers were 10-20 times higher than non-smokers. These blood cadmium values stand in sharp contrast to what has been published so far and make the average smokers of Canadian-made cigarettes medically unfit for employment in jobs associated with potential cadmium exposure.

Blood and urinary cadmium levels in Inuit living in Kuujjuaq, Canada.

Blood and urine cadmium concentrations have been determined in a group of 85 Inuit residents of Kuujjuaq, Quebec, Canada, drawn from actively hunting households. Mean blood cadmium values are high at 39.4 nmol/l, varying between 6.6 in non-smokers and 60.3 in smokers. No association of blood cadmium with self-reported offal consumption could be found. Median urine cadmium concentrations are elevated at 2.3 mumol/mol creatinine and rise substantially with age: 0.9 in the 30-39 age group; 3.2 among the 40-59 age group; and 4.1 in the 60 and over.

Pattern of cadmium contamination in the liver and kidneys of moose and white-tailed deer in Québec.

Samples of moose (N = 431) and white-tailed deer (N = 225) liver and kidneys were collected during the 1985 hunting season from 14 zones south of the 50 degree latitude in Québec. Regional differences in cadmium level in the liver were detected and three homogeneous areas were delineated for each species. Uptake was greater for moose than for deer: in the liver, mean concentrations were 2.9-15.9 mg kg-1 (dry weight) for moose and 0.8-2.6 for deer, depending on the area and sex; in kidneys, means ranged between 31.8-100.5 and 20.9-39.0 mg kg-1, respectively. Female moose had lower levels than bulls. Less affected moose, in eastern Québec, contained cadmium concentrations comparable to the highest values measured in Scandinavia. Cadmium uptake in deer was on the same level or higher than in the United States. Our results indicate a widespread presence of this heavy metal in the environment that may be linked to acid precipitation. We do not recommend consuming wild cervid liver or kidneys in Québec for the moment. Further research is needed on the overall mechanisms involved in the cadmium contamination of the environment and on the actual intake of this metal in the human diet.

Variation in cadmium content of caribou tissues from northern Québec.

Samples of kidney, liver, skeletal muscle, heart, mesentery and rumen wall were collected during 1985-1986 in northern Québec from 121 caribou belonging to the Rivière George herd. Significant seasonal variations were found for cadmium concentration in kidneys, liver and skeletal muscles, the level being higher in winter than in autumn. The concentration in liver and kidneys increased with age, while the effect of this factor was complex in skeletal muscles. Sex-related differences were found in muscle and liver levels of cadmium. According to season, sex and age, mean dry-weight concentrations varied between 5.6 and 51.3 micrograms g-1 in kidneys, 1.7 and 4.0 micrograms g-1 in liver and 0 and 0.27 microgram g-1 in skeletal muscles. Season and sex-related differences could be explained by seasonal variation in cadmium intake and by the annual weight cycle exhibited by caribou kidneys and liver. Because of the relatively high cadmium content, it was recommended not to consume liver and kidneys of free-ranging caribou in Québec; this restriction did not apply to meat, heart, mesentery or rumen wall that contained limited concentrations of this heavy metal.

Anatomic considerations of plate-screw fixation of the anterior column of the acetabulum.

Fifteen cadaveric adult bony hemipelvis specimens and 30 adult dry bone specimens were obtained to evaluate the configuration of the anterior column of the acetabulum and to develop a safe path for screw placement into it. Each cadaveric specimen was sectioned at 1-cm intervals, beginning at the level of the inferior border of the acetabulum (junction between the anteroinferior edge of the acetabulum and the most anterolateral edge of the superior ramus of the pubic bone). The plane of the cross-section was perpendicular to the anterior column. The projection of the medial acetabular boundary on the anterior column was determined by analysis of each cross-section. Results showed that the average width of the anterior column at 1.0, 2.0, and 3.0 cm superior to the inferior acetabular boundary is 31.0 +/- 4.7, 34.2 +/- 5.1, and 39.4 +/- 6.2 mm, respectively. At 1.0 cm superior to the inferior margin of the acetabulum, the average medial angulation for 0.5-, 1.0-, and 1.5-cm entry points lateral to the pelvic brim were 24.9 +/- 4.4 degrees, 35.5 +/- 5.2 degrees, and 44.4 +/- 6.6 degrees, respectively. At 2.0 cm superior to the inferior acetabular margin, the corresponding average medial angulation for 0.5-, 1.0-, 1.5-cm entry points were determined to be 29.2 +/- 5.5 degrees, 38.6 +/- 5.9 degrees, and 48.1 +/- 5.7 degrees, respectively. At 3.0 cm superior to the inferior acetabular margin, these angles were found to be 20.7 +/- 4.3 degrees, 29.4 +/- 6.0 degrees, and 39.3 +/- 5.9 degrees, respectively. All of the above mentioned angles are with respect to the perpendicular of the longitudinal axis of the anterior column without violation of the hip joint. Screws placed 1.0 cm lateral to the pelvic brim at the levels of 1.0, 2.0, 3.0, and 4.0 cm superior to the inferior acetabular margin and directed perpendicular to the anterior column penetrated the hip joint.

[Garcin syndrome--a case report]. / Garcin-Syndrom--eine Fallvorstellung.

The case of a 68 year-old woman with Garcin syndrome on the basis of a metastasis of the skull from a mammary carcinoma is described in detail. Most cases of unilateral multiple brain nerve lesions are due to primary or secondary bone tumours, a few cases are of an inflammatory origin. In the majority of cases not all twelve brain nerves are affected. The various syndromes with different localization on the basis of the skull are listed in a table. The destruction of the base of skull may be seen on plain X-rays or on a computed tomogram.

Strategies for the selection of log-linear models.

In a multidimensional contingency table strategies have been proposed to build log-linear models using either stepwise methods or standardized estimates of the parameters of the saturated model. Brown (1976) proposed a two-step procedure to screen effects and then test a subset of models. Alternate methods of model building are discussed with respect to the final choice of model and with respect to intermediate information available to the data analyst during the selection process.

Recurrence rates in genital herpes after symptomatic first-episode infection.

OBJECTIVE: To evaluate the frequency of reactivation of genital herpes infection and to identify predictors for recurrence. DESIGN: Prospective, observational cohort study. SETTING: Research clinic. PATIENTS: 457 consecutive patients who did not have acute-phase serum antibodies to herpes simplex virus type 2 (HSV-2) but who did have herpes simplex virus (HSV) isolated from genital lesions. RESULTS: Eighty-nine percent of patients with HSV-2 had at least one recurrence during follow-up (median, 391 days); the median monthly recurrence rate was 0.34. Thirty-eight percent had at least 6 recurrences during the first year and 20% had more than 10 recurrences. The median monthly recurrence rate was 0.43 for men and 0.33 for women (difference, 0.10 [95% CI, 0.03 to 0.19]; P < 0.01). Twenty-six percent of women and 8% of men had no or 1 recurrence in year 1 of follow-up, whereas 14% of women and 26% of men had more than 10 recurrences. Patients who had severe primary HSV-2 infection (duration, > or = 35 days) had recurrences nearly twice as often (0.66 compared with 0.36 recurrences per month [95% CI, 0.18 to 0.57]) and had a shorter time to first recurrence when compared with those who had shorter first episodes. CONCLUSIONS: Almost all persons with initially symptomatic HSV-2 infection have symptomatic recurrences. More than 35% of such patients have frequent recurrences. Recurrence rates are especially high in persons with an extended first episode of infection, regardless of whether they receive antiviral chemotherapy with acyclovir. Men with genital HSV-2 infection have about 20% more recurrences than do women, a factor that may contribute to the higher rate of HSV-2 transmission from men to women than from women to men and to the continuing epidemic of genital herpes in the United States.