René Gonin

Discordance in the histopathologic diagnosis of melanoma and melanocytic nevi between expert pathologists

The reliability of a diagnostic test depends on the reproducibility of the result. Many clinical diagnostic tests can be quantified with established ranges and standard deviations. Other tests are more subjective, such as those that depend on analysis of a visual image with an increased possibility of variance in the result. To study this variance, the authors analyzed the performance of expert pathologists in the interpretation of cutaneous melanocytic tumors. A panel of expert pathologists was convened to review anatomic pathology specimens from melanocytic tumors. Each pathologist submitted five specimens, from which 37 were selected for review. Only one slide was used for each case. All specimens were interpreted by each pathologist without consultation with each other. In addition to standard diagnostic terms, each specimen was designated as benign, malignant, or indeterminate. Statistical analysis was used to determine the degree of concordance. The combined kappa statistic for the eight observers and three possible outcomes (benign, malignant, or indeterminate) was 0.50. A kappa statistic of this magnitude, is defined as being moderate. In 62% of the specimens, there was unanimous agreement or only one discordant designation. Thirty-eight percent had two or more discordant interpretations. No single pathologist had a disproportionate number of discordant designations. This study mimics the consultation practice of anatomic pathology and shows the variability and discordance in diagnostic language and designation of biological behavior. The results suggest the criteria for the diagnosis of melanomas and melanocytic nevi need to be refined and more consistently applied.

Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor.

PURPOSE This study was designed to assess the effectiveness of vinblastine, ifosfamide, and cisplatin (VeIP) as second-line therapy in patients with recurrent germ cell tumors with previous treatment with cisplatin plus etoposide, usually in combination with bleomycin. PATIENTS AND METHODS From July 1984 through December 1989, 135 patients with progressive, disseminated germ cell tumors after cisplatin-etoposide-based combination therapy induction chemotherapy were treated with VeIP. Patients who progressed within 3 weeks of previous cisplatin therapy were not eligible. Progression was documented by biopsy or increasing serum markers. No exclusion was made on the basis of metastatic site or performance status. The dosages were vinblastine 0.11 mg/kg/d (days 1 and 2), ifosfamide 1.2 gm/m2/d (days 1 through 5), and cisplatin 20 mg/m2/d (days 1 through 5), with courses repeated every 21 days for four cycles. RESULTS Sixty-seven (49.6%) patients achieved a disease-free status after chemotherapy with or without surgical resection of residual carcinoma or teratoma. Overall, 42 (32%) patients are alive and 32 (23.7%) are continuously free of disease. None of the 32 patients with nonseminomatous extragonadal tumors are disease-free compared with 30 of 100 patients with gonadal primaries. Two of three extragonadal seminomas are continuously disease-free. CONCLUSION VeIP is capable of producing durable complete remissions in patients with disseminated germ cell cancer who relapse after cisplatin-etoposide-based induction therapy. Long-term disease-free survival is not seen in those patients with extragonadal nonseminomatous germ cell tumors.

Late relapse of testicular cancer.

PURPOSE This study analyzed a large group of patients with testicular germ cell cancer in complete remission, who relapsed more than 2 years after completion of treatment. PATIENTS AND METHODS A review of all patients treated at Indiana University Medical Center from 1979 through 1992 for late relapse was conducted. Eighty-one patients were treated for late relapse of testicular cancer. Forty-seven patients relapsed more than 5 years after successful management of their initial disease. RESULTS At initial diagnosis, 35 patients had clinical stage I, 18 stage II, and 28 stage III disease. Twenty-three of 35 stage I, all 18 stage II, and all 28 stage III patients were treated by chemotherapy before their late relapse. The median follow-up duration of patients post-management of late relapse was 4.8 years. Twenty-one patients (25.9%) are continuously disease-free. Nineteen of these 21 patients had surgical resection of carcinoma or teratoma as a component of their therapy. Of sixty-five patients treated for late relapse by chemotherapy, 17 (26.2%) had a complete response, but only two have been continuously disease-free with chemotherapy alone. These two never received prior chemotherapy. CONCLUSION Late relapse of testis cancer is more common than previously thought. Surgery is the preferred mode of therapy. Chemotherapy has only modest success in this entity, in contrast to the excellent results in de novo germ cell tumors. Patients treated for testicular germ cell cancer need annual follow-up evaluations throughout their life due to the possibility of late relapse.

Nurse versus doctor management of HIV-infected patients receiving antiretroviral therapy (CIPRA-SA): A randomised non-inferiority trial

BACKGROUND Expanded access to combination antiretroviral therapy (ART) in resource-poor settings is dependent on task shifting from doctors to other health-care providers. We compared outcomes of nurse versus doctor management of ART care for HIV-infected patients. METHODS This randomised non-inferiority trial was undertaken at two South African primary-care clinics. HIV-positive individuals with a CD4 cell count of less than 350 cells per microL or WHO stage 3 or 4 disease were randomly assigned to nurse-monitored or doctor-monitored ART care. Patients were randomly assigned by stratified permuted block randomisation, and neither the patients nor those analysing the data were masked to assignment. The primary objective was a composite endpoint of treatment-limiting events, incorporating mortality, viral failure, treatment-limiting toxic effects, and adherence to visit schedule. Analysis was by intention to treat. Non-inferiority of the nurse versus doctor group for cumulative treatment failure was prespecified as an upper 95% CI for the hazard ratio that was less than 1.40. This study is registered with ClinicalTrials.gov, number NCT00255840. FINDINGS 408 patients were assigned to doctor-monitored ART care and 404 to nurse-monitored ART care; all participants were analysed. 371 (46%) patients reached an endpoint of treatment failure: 192 (48%) in the nurse group and 179 (44%) in the doctor group. The hazard ratio for composite failure was 1.09 (95% CI 0.89-1.33), which was within the limits for non-inferiority. After a median follow-up of 120 weeks (IQR 60-144), deaths (ten vs 11), virological failures (44 vs 39), toxicity failures (68 vs 66), and programme losses (70 vs 63) were similar in nurse and doctor groups, respectively. INTERPRETATION Nurse-monitored ART is non-inferior to doctor-monitored therapy. Findings from this study lend support to task shifting to appropriately trained nurses for monitoring of ART. FUNDING National Institutes of Health; United States Agency for International Development; National Institute of Allergy and Infectious Diseases.

The Relationship of Acute Transfusion-Associated Hepatitis to the Development of Cirrhosis in the Presence of Alcohol Abuse

Seroprevalence data from the Third National Health and Nutrition Examination Survey (1984 to 1999) suggest that 3 million persons in the United States are infected with the hepatitis C virus (HCV) (1). Treatment fails to clear the virus in 80% to 85% of acutely infected persons. Not all persons who remain infected eventually develop progressive liver disease (2), but in those who do, clinical evidence of liver damage may not appear until decades later (3). It is widely believed that progression of liver disease in persons with chronic HCV infection is enhanced by concomitant heavy alcoholism (4-12). We sought to quantify the association of transfusion-associated HCV infection and history of alcohol abuse with development of cirrhosis among patients followed from the time of acute HCV infection. Methods The source of this investigation, described in detail elsewhere (13), is a long-term follow-up study of acute non-A, non-B hepatitis in patients included in earlier prospective studies of transfusion-related HCV infection. All patients provided informed consent, and the study was approved by the relevant institutional review boards. Briefly, non-A, non-B hepatitis was identified by otherwise unexplained elevations in serum alanine aminotransferase (ALT) levels developing 2 to 24 weeks after transfusion, in the absence of serologic evidence of hepatitis A or B (13). The ALT level had to be elevated on two consecutive measurements, and at least one of the values had to exceed twice the upper limit of normal. Stored sera from case-patients and controls from three of the prospective studiesthe second Veterans Administration Cooperative study (14), the Transfusion-Transmitted Viruses study (15), and the National Institutes of Health Blood Bank Study (16)were tested for anti-HCV by enzyme immunoassay (HCV EIA 2.0, Abbott Laboratories, North Chicago, Illinois). Transfusion-associated HCV infection was diagnosed if anti-HCV appeared and persisted, was temporally related to elevated ALT levels, and was confirmed by using the supplementary recombinant immunoblot assay (RIBA version 3.0, Ortho Diagnostics, Raritan, New Jersey). Because repository samples were not optimally stored for minimizing nucleic acid loss, HCV RNA testing was not performed. Controls consisted of transfused patients from the original three prospective studies who had not developed hepatitis (13). Controls were matched to case-patients by initial treatment center, sex, ethnicity, use of hepatitis immune globulin, presence or absence of a history of alcoholism, age, number of units of blood transfused, and date of transfusion. We excluded patients with anti-HCVpositive samples that predated the index transfusion and those with anti-HCV reactivity but no confirmatory test. Anti-HCVpositive/RIBA-negative and anti-HCVnegative patients were classified as having transfusion-associated non-A, non-B, non-C hepatitis. Controls with anti-HCV in repository samples were excluded. We used a multifaceted approach to gather information on each patients history of liver disease from participation in the prospective studies through initiation of the follow-up study (13). Vital status was ascertained through searches of death registries, and copies of death certificates were obtained. Patients or their designated proxies (if the patient was deceased or incompetent) were invited to participate in a personal interview that included questions about previous hospitalizations. Authorization for release of medical records was obtained, and information on all hospitalizations at each facility identified was requested. Medical records, death certificates, and biopsy and autopsy reports were reviewed by trained abstractors for the diagnosis of cirrhosis, which was based on the occurrence of features of portal hypertension and overt clinical manifestations of cirrhosis. Evaluation of a sample of records indicated a high level of agreement between abstractors and one of the investigators. Potential risk factors were derived primarily from personal interview. A composite variable aimed at identifying a history of heavy alcohol abuse was designed to minimize the possibility of misclassifying unexposed patients. The composite variable was based on one or more of the following criteria: loss of friends, family, or a job because of drinking; admitting to ever having a problem with alcoholism; evidence of heavy drinking abstracted from medical records; or quantification of usual intake of more than 80 g of alcohol per day during the years when the patient drank. Univariate methods (the Fisher exact, exact FisherFreemanHalton [17], and Wilcoxon rank-sum tests) were used to compare the distribution of characteristics between patients included in and those excluded from the analysis and to examine associations between potential risk factors and development of cirrhosis. The strength of the association between risk factors and cirrhosis was assessed by using the odds ratio obtained from multiple logistic regression. The likelihood of developing cirrhosis associated with a combination of risk factors was estimated from the logistic model (18). Results Of 1030 patients who were followed up from the original prospective studies that had collected repository samples, 836 (81.2%) were included in this analysis. We excluded 108 patients whose repository samples were exhausted, 79 with ALT levels or HCV assays that did not permit reliable classification of hepatitis status, 1 with cirrhosis that predated the index transfusion, and 6 with data inconsistencies that could not be resolved. As shown in Table 1, included and excluded patients differed only in median number of blood units originally transfused. The number of units received could affect the probability of developing acute transfusion-associated hepatitis or its severity but would probably not influence development of cirrhosis decades later. Table 1. Characteristics of Included and Excluded Patients Preliminary analyses indicated that development of cirrhosis was unrelated to tattooing, ear piercing, occupational exposures, extended travel to areas in which hepatitis is endemic, and use of injection or other illegal drugs. Information on prescription drug use was unavailable for analysis. Development of cirrhosis differed (P<0.05) according to transfusion-associated hepatitis status, study cohort, race/ethnicity, units of blood originally transfused, history of heavy alcohol abuse, and vital status at follow-up (Table 2). The absolute risk for developing cirrhosis was higher among patients with transfusion-associated HCV infection (17.0% [35 of 206 patients]) (P<0.001) than among those with transfusion-associated non-A, non-B, non-C hepatitis infection (3.2% [3 of 95 patients]) or controls (2.8% [15 of 535 patients]) but did not differ between the latter two groups (P>0.2). The median time from index transfusion to initiation of follow-up (15.6 years overall) did not differ by cirrhosis status, transfusion-associated hepatitis status, or race/ethnicity (P 0.10). Table 2. Association of Patient Characteristics with Development of Cirrhosis Logistic regression modeling indicated that patients with transfusion-associated HCV infection were 7.8 times (95% CI, 4.0 to 15.1 times) more likely to develop cirrhosis than controls, after adjustment for history of heavy alcohol abuse and study cohort. Patients with transfusion-associated non-A, non-B, non-C hepatitis were at increased risk for developing cirrhosis, but this finding was not significant (odds ratio, 1.4 [95% CI, 0.4 to 5.0]). Patients with transfusion-associated HCV were 5.6 times (CI, 1.6 to 19.3 times) more likely to develop cirrhosis than those with non-A, non-B, non-C hepatitis. A history of heavy alcohol abuse was associated with an increased risk for developing cirrhosis (odds ratio, 4.0 [CI, 2.1 to 7.7]). The HosmerLemeshow goodness-of-fit test indicated that the model fit the data well (P>0.2). From this model, it was estimated that patients with both transfusion-associated HCV infection and a history of heavy alcohol abuse were 31.1 times (CI, 11.4 to 84.5 times) more likely to develop cirrhosis than controls without a history of alcohol abuse. Patients with transfusion-associated non-A, non-B, non-C hepatitis and a history of heavy alcohol abuse were also more likely than controls without such a history to develop cirrhosis (odds ratio, 5.5 [CI, 1.3 to 24.3]). Although cirrhosis was less common among African-Americans (2.2%) than among persons of other ethnicities (7.2%), addition of race/ethnicity, follow-up duration, units of blood originally transfused, vital status, and receipt of additional transfusions to the model changed the risks associated with hepatitis status and history of heavy alcohol abuse only slightly. None of these factors made a significant independent contribution to the model (data not shown). Discussion Patients who contracted transfusion-associated HCV infection were at increased risk for developing cirrhosis (odds ratio, 7.8), and this risk increased substantially if the patient also had a history of heavy alcohol abuse (odds ratio, 31.1). Although numerous reports have identified a strong role of alcohol in promoting progression of liver disease among persons with chronic HCV infection (4-12), our findings provide a quantitative measure to assess the strength of this association. Some patients who were originally classified as having acute non-A, non-B hepatitis tested negative for HCV infection. These patients developed cirrhosis more frequently than controls, but not significantly so. This finding suggests that the elevated ALT levels observed during the original prospective studies were caused by intrinsic liver disease. It remains to be determined, however, whether these patients had been infected with a virus other than hepatitis A, B, or C virus or whether the elevated enzyme levels resulted from other causes (for example, nonviral infection

Positron emission tomography evaluation of residual radiographic abnormalities in postchemotherapy germ cell tumor patients

PURPOSE This study was performed to assess the ability of positron emission tomography (PET) to differentiate residual radiographic abnormalities in postchemotherapy nonseminomatous germ cell tumor (GCT) patients. MATERIALS AND METHODS Thirty patients with nonseminomatous GCT were evaluated with PET scans before surgical resection of a residual mass or masses. Standardized uptake values (SUV) were calculated for the region of maximal 2-fluoro-2-deoxyglucose (FDG) uptake and compared with histologic findings. RESULTS Eleven patients had necrosis/fibrosis in the resected specimen, 15 had teratoma, and four viable GCT. The median SUV for the necrosis/fibrosis group was 2.86, teratoma 3.07, and viable GCT 8.81. A significant association between SUV and histology was found when comparing viable GCT versus necrosis/fibrosis plus teratoma (P = .004). Patients with an SUV greater than 5 were 75 times more likely to have viable cancer than teratoma or necrosis/fibrosis (odds ratio; 95% confidence interval, 3.66 to 1,536). PET did not differentiate necrosis/fibrosis from teratoma. However, PET was able to differentiate viable GCT from residual necrosis/fibrosis or teratoma. CONCLUSION PET-FDG imaging can be useful for detection of residual viable carcinoma following chemotherapy in nonseminomatous GCT patients with residual masses. It may be a valuable adjunct in the determination of which patients should undergo postchemotherapy resection.

Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: the Indian University experience.

PURPOSE In a previously reported randomized Southeastern Cancer Study Group (SECSG) trial, three cycles of chemotherapy were found to be equivalent to four cycles in patients with favorable-prognosis germ-cell cancer. We have conducted a follow-up analysis of patients treated at Indiana University (Indianapolis, IN) to compare long-term survival between the two groups and to examine factors associated with survival. PATIENTS AND METHODS Sixty-nine patients with minimal-stage and 49 patients with moderate-stage disseminated germ-cell tumors were randomized to either three or four courses of bleomycin, etoposide, and cisplatin (BEP) administered every 3 weeks. Median follow-up time is 10.1 years (range, 7 months to 12.6 years). Ninety-two percent of patients have an actual follow-up time of > 5 years, and 97.5% of patients have an actual follow-up time of > 3 years. RESULTS Survival analysis shows no significant difference between the two treatment groups in terms of overall (P = .80) or disease-free (P = .93) survival. Several clinical variables were examined by univariate analysis; only serum human chorionic gonadotropin (HCG) had an impact on survival. There were two disease-related deaths in 104 patients with HCG < or = 1,000 mIU/mL and five disease-related deaths in 14 patients with HCG greater than 1,000 mIU/mL (P < .001). Ninety-eight percent (95% CI, 95.2 to 100) of patients with favorable prognosis germ-cell tumor with an initial HCG of < or = 1,000 mIU/mL are alive without evidence of disease at 5+ years. CONCLUSION With long-term follow-up, there is no statistically significant difference in survival between three or four cycles of BEP chemotherapy in patients with favorable prognosis germ-cell carcinoma. Serum HCG elevation of greater than 1,000 mIU/mL is a significant predictor of poor outcome in patients with otherwise good-risk disease.

Cisplatin plus etoposide with and without ifosfamide in extensive small-cell lung cancer: a Hoosier Oncology Group study.

PURPOSE To determine whether the addition of ifosfamide to cisplatin plus etoposide improves the response rate, time to disease progression, or overall survival in previously untreated patients with extensive-stage small-cell carcinoma of the lung (SCLC). PATIENTS AND METHODS Patients with extensive SCLC with a Karnofsky performance score (KPS) > or = 50 and adequate renal function and bone marrow reserve were eligible. Patients with CNS metastases were eligible and received concurrent whole-brain radiotherapy. Patients were randomized to receive cisplatin (20 mg/m2) plus etoposide (100 mg/m2) (VP) both given intravenously (i.v.) on days 1 to 4 or cisplatin (20 mg/m2), ifosfamide (1.2 g/m2), and etoposide (75 mg/m2) (VIP) all given i.v. on days 1 to 4. Cycles were repeated every 3 weeks for four cycles. RESULTS From May 1989 through March 1993, 171 patients were randomized (84 to VP and 87 to VIP). The median follow-up duration is 26 months. All patients were assessable for survival; 163 were fully assessable for response and 162 for toxicity. Myelosuppression was greater with VIP. Objective responses were observed in 55 of 82 (67%) and 59 of 81 (73%) assessable patients treated with VP and VIP, respectively (difference not significant). The difference in the median time to progression was statistically different (P = .039). The median survival times on VP and VIP were 7.3 months and 9.0 months, respectively (P = .045 for survival curves by stratified log-rank test) with 2-year survival rates of 5% versus 13%, respectively. CONCLUSION VIP combination chemotherapy is associated with an improved time to progression and overall survival over VP therapy in patients with extensive SCLC.

Salvage chemotherapy with vinblastine, ifosfamide, and cisplatin in recurrent seminoma.

PURPOSE Salvage therapy for disseminated germ cell tumors of all histologic subtypes with vinblastine, ifosfamide, and cisplatin (VeIP) will cure approximately 25% of patients. The purpose of this study was to evaluate the activity of VeIP in patients with recurrent seminoma. PATIENTS AND METHODS We conducted a retrospective review of 24 patients with recurrent seminoma who were treated at Indiana University with VeIP as second-line chemotherapy. All patients had received cisplatin-containing regimens as primary chemotherapy and seven had also received prior pelvic radiotherapy. All patients received four courses of VeIP. RESULTS The minimum follow-up duration was 2 years (range, 2 to 9.1), with a median follow-up time of 7 years. Twenty of 24 patients (83%) achieved a complete remission (CR) following VeIP alone. One additional patient was rendered disease-free (NED) with the resection of residual carcinoma. Eight patients have relapsed. Four of six patients with extragonadal primary tumors and two of four who failed to achieve CR with initial chemotherapy are continuously NED with VeIP. Overall, 13 of 24 (54%) are long-term survivors with VeIP salvage chemotherapy. CONCLUSION VeIP has significant curative potential in patients with recurrent seminoma and appears to produce a higher CR rate and more long-term survivors than is achieved in patients with nonseminomatous disease.

Maternal antiretroviral drugs during pregnancy and infant low birth weight and preterm birth

Objective:To determine the relationship between maternal antiretroviral regimens during pregnancy and adverse infant outcomes [low birth weight (LBW) and preterm birth]. The a priori hypothesis was that protease inhibitor (PI)-containing regimens are associated with an increased risk of LBW and preterm birth. Design:Prospective cohort study of HIV-1-infected women and their infants (NISDI Perinatal Study). Methods:Data were analysed from 681 women receiving at least one antiretroviral drug [in order of increasing complexity: one or two nucleoside reverse transcriptase inhibitors (1–2 NRTI), two NRTI plus one non-nucleoside reverse transcriptase inhibitor (NNRTI) (HAART/NNRTI), or two NRTI plus one PI (HAART/PI)] for at least 28 days during pregnancy, and who delivered live born, singleton infants with known birth weight and gestational age by 1 March 2005. Multivariable logistic regression modeling was used to assess the relationship of maternal ART with LBW and with preterm birth, adjusting for covariates. Results:The incidence of LBW and preterm birth, respectively, was 9.6% and 7.4% (1–2 NRTI), 7.4% and 5.8% (HAART/NNRTI), and 16.7% and 10.6% (HAART/PI). There was no statistically significant increased risk of LBW [adjusted odds ratio (AOR), 1.5; 95% confidence interval (95% CI), 0.7–3.2] or preterm birth (AOR, 1.1; 95% CI, 0.5–2.8) among women who received HAART/PI compared with women receiving 1–2 NRTI. Conclusions:Among a population of HIV-1-infected women in Latin America and the Caribbean, maternal receipt of PI-containing ART regimens during pregnancy was not associated with a statistically significant increase in risk of LBW or preterm birth.