A risk prediction model for the development of subsequent primary melanoma in a population-based cohort.

BACKGROUND: Guidelines for follow-up of patients with melanoma are based on limited evidence. OBJECTIVES: To guide skin surveillance, we developed a risk prediction model for subsequent primary melanomas, using demographic, phenotypical, histopathological, sun exposure and genomic risk factors. METHODS: Using Cox regression frailty models, we analysed data for 2613 primary melanomas from 1266 patients recruited to the population-based Genes, Environment and Melanoma study in New South Wales, Australia, with a median of 14 years' follow-up via the cancer registry. Discrimination and calibration were assessed. RESULTS: The median time to diagnosis of a subsequent primary melanoma decreased with each new primary melanoma. The final model included 12 risk factors. Harrell's C-statistic was 0·73 [95% confidence interval (CI) 0·68-0·77], 0·65 (95% CI 0·62-0·68) and 0·65 (95% CI 0·61-0·69) for predicting second, third and fourth primary melanomas, respectively. The risk of a subsequent primary melanoma was 4·75 times higher (95% CI 3·87-5·82) for the highest vs. the lowest quintile of the risk score. The mean absolute risk of a subsequent primary melanoma within 5 years was 8·0 ± SD 4.1% after the first primary melanoma, and 46·8 ± 15·0% after the second, but varied substantially by risk score. CONCLUSIONS: The risk of developing a subsequent primary melanoma varies considerably between individuals and is particularly high for those with two or more primary melanomas. The risk prediction model and its associated nomograms enable estimation of the absolute risk of subsequent primary melanoma, on the basis of on an individual's risk factors, and can be used to tailor surveillance intensity, communicate risk and provide patient education. What's already known about this topic? Current guidelines for the frequency and length of follow-up to detect new primary melanomas in patients with one or more previous primary melanomas are based on limited evidence. People with one or more primary melanomas have, on average, a higher risk of developing another primary invasive melanoma, compared with the general population, but an accurate way of estimating individual risk is needed. What does this study add? We provide a comprehensive risk prediction model for subsequent primary melanomas, using data from 1266 participants with melanoma (2613 primary melanomas), over a median 14 years' follow-up. The model includes 12 risk factors comprising demographic, phenotypical, histopathological and genomic factors, and sun exposure. It enables estimation of the absolute risk of subsequent primary melanomas, and can be used to tailor surveillance intensity, communicate individual risk and provide patient education.

Publication bias and dissemination of clinical research.

Publication bias is a widely recognized phenomenon that occurs because of the influence of study results on the chances of publication. Usually, studies with positive results are more likely to be published than studies with negative results, which leads to a preponderance of false-positive results in the literature. Empiric studies have demonstrated that the induced bias is large and can have a serious impact on meta-analyses, in which data from several studies are aggregated, as well as on informal reviews. The problem is deeply embedded in current research practice, which encourages demonstration of statistical significance to "prove" theories, and one of its causes is the pressure to publish extensively that is an integral part of the competition for academic promotion. Serious efforts to reduce this problem will involve restructuring the process by which study results are disseminated, changing editorial policies, and altering the style and methods of statistical analysis.

Age and adjuvant chemotherapy use after surgery for stage III colon cancer.

BACKGROUND: Randomized trials have established that 5-fluorouracil-based adjuvant chemotherapy following resection of stage III colon cancer reduces subsequent mortality by as much as 30%. However, the extent to which adjuvant therapy is used outside the clinical trial setting, particularly among the elderly, is unknown. METHODS: A retrospective cohort study utilizing the Surveillance, Epidemiology, and End Results/Medicare-linked database identified 6262 patients aged 65 years and older with resected stage III colon cancer. The primary outcome was chemotherapy use within 3 months of surgery, as ascertained from Medicare claims. We examined the extent to which age at diagnosis was associated with adjuvant chemotherapy usage, and we adjusted for potential confounding based on differences in other patient characteristics with the use of multiple logistic regression. All P values were two-sided. RESULTS: Age at diagnosis was the strongest determinant of chemotherapy: 78% of patients aged 65-69 years, 74% of those aged 70-74 years, 58% of those aged 75-79 years, 34% of those aged 80-84 years, and 11% of those aged 85-89 years received postoperative chemotherapy. The age trend remained pronounced after adjustment for potential confounding based on variation in patients' demographic and clinical characteristics and after exclusion of patients with any evident comorbidity (all P values <.001). CONCLUSIONS: Adjuvant chemotherapy for stage III colon cancer is used extensively, especially for patients under the age of 75 years. However, treatment rates decline dramatically with chronologic age. Because patients in their 70s and even 80s have a reasonable life expectancy, further efforts are needed to ensure that elderly patients have the opportunity to make informed decisions regarding this potentially curative treatment.

Screening for cutaneous melanoma by skin self-examination.

BACKGROUND: Although some evidence indicates that early detection protects against the development of lethal melanoma, no randomized clinical trials have been conducted to measure the efficacy of early detection (or screening) in preventing death from this disease. Since melanoma incidence in the United States is relatively rare, a randomized clinical trial to test the efficacy of screening would be extremely expensive. PURPOSE: As an alternative to a randomized clinical trial, we conducted a population-based, case-control study to investigate whether early detection through skin self-examination (SSE) is associated with a decreased risk of lethal melanoma (includes the presence of advanced disease with distant metastases in addition to death from melanoma). METHODS: SSE (conducting a careful, deliberate, and purposeful examination of the skin) was assessed in all subjects by use of a structured questionnaire and personal interviews. The major exposure variable, SSE, was defined following focus-group interviews with melanoma patients and healthy control subjects. The final study population consisted of 1199 Caucasian residents of the state of Connecticut enrolled from January 15, 1987, through May 15, 1989; 650 individuals were newly diagnosed with cutaneous melanoma, and the remaining 549 individuals were age- and sex-frequency matched control subjects from the general population. During the study interviews, nevi on the arms and backs of subjects were counted. In 5 years of follow-up (through March 1994), 110 lethal cases of melanoma were identified. The study design allowed separate estimation of the impact of SSE on reduced melanoma incidence (primary prevention) and survival among incident cases (secondary prevention). Odds ratios (ORs) were used to measure the associations between SSE and melanoma and between SSE and lethal melanoma. RESULTS: SSE, practiced by only 15% of all subjects, was associated with a reduced risk of melanoma incidence (adjusted OR = 0.66; 95% confidence interval [CI] = 0.44-0.99; comparing case patients with control subjects). The data indicated further that SSE may reduce the risk of advanced disease among melanoma patients (unadjusted risk ratio = 0.58; 95% CI = 0.31-1.11); however, longer follow-up is required to confirm this latter estimate. If both estimates are correct, they suggest, in combination, that SSE may reduce mortality from melanoma by 63% (adjusted OR = 0.37; 95% CI = 0.16-0.84; comparing lethal cases with general population controls). CONCLUSIONS AND IMPLICATIONS: SSE may provide a useful and inexpensive screening method to reduce the incidence of melanoma. SSE may also reduce the development of advanced disease. The results of this study need to be replicated before strategies to increase the practice of SSE are further developed and promoted.

Eastern Cooperative Oncology Group study of the cytochemistry of adult acute myeloid leukemia by correlation of subtypes with response and survival.

A study of over 300 adult patients with acute myeloid leukemia has been completed by member institutions of the Eastern Cooperative Oncology Group. A complete remission rate of 51% was achieved. The FAB classification was used with an overall concordance of 61% between investigators and the repository center. Acute monocytic leukemia (M5) and acute erythroleukemia (M6) accounted for 12% of the cases accessioned and had the worst median survival with no patients surviving 2 years. The longest response duration occurred in hypergranular promyelocytic leukemia (M3).

Surface marker identification of small cleaved follicular center cell lymphomas with a highly favorable prognosis.

Between 1976 and 1980, 143 cases of non-Hodgkin's lymphoma have been prospectively analyzed for correlations between surface marker phenotype, histomorphology, and prognosis. This study analyzed 44 adults with tumors classified by Lukes-Collins criteria as small cleaved follicular center cell lymphomas. Two surface marker phenotypic subsets were membrane immunoglobulin, immunoglobulin D (IgD), or a receptor for the third component of the complement system (C'3) (Group I = IgD+ and/or C'3+, group II = IgD-C'3-). Eleven of the 44 patients have died with a projected median survival of 58 months. Four patients in Group I have died with a median survival of 58 months while seven patients in Group II have died with a median survival of 30 months. The difference in the survival curves for the two subgroups is statistically significant (p = 0.01). An analysis of variables such as stage, age, sex, and sites of involvement revealed no differences between the two groups. When classified histologically, the two groups were morphologically indistinguishable and had similar distributions of nodular (follicular) and diffuse variants. Of interest, five patients in Group I were judged to require no initial therapy whereas none in Group II remained untreated initially. The expression of the second heavy chain delta and/or a receptor for C'3 appears to define a subgroup of small cleaved follicular center cell lymphomas with an indolent course and an excellent prognosis.

High peripheral blast count in adult acute myelogenous leukemia is a primary risk factor for CNS leukemia.

The lengthening remission duration achievable in acute myelogenous leukemia (AML) places patients at risks for CNS leukemic relapse. We reviewed the data on two Eastern Cooperative Oncology Group (ECOG) trials in acute nonlymphocytic leukemia to determine the incidence of CNS leukemia (CNSL). The incidence of CNSL was 5% (30 of 569 patients) overall, and 3% (ten of 331) in patients in complete remission (CR). A number of factors were evaluated for association with increased risk of CNSL. Men more frequently developed CNSL than women at a three to one ratio, and median presenting WBC counts were higher in affected than unaffected patients (44,200/microL v 17,000/microL, P = .01). The low incidence of CNSL in AML supports the view that CNS prophylaxis is unnecessary. However, because 68% of patients (13 of 19) who developed CNSL early in the course of disease had presenting WBC counts greater than 40,000/microL, screening lumbar punctures should be routinely obtained during induction therapy in patients presenting with high circulating blast cell counts.

A critical comparison of allogeneic bone marrow transplantation and conventional chemotherapy as treatment for acute nonlymphocytic leukemia.

Published data from two centers conducting bone marrow transplantation on patients with acute nonlymphocytic leukemia in first remission were pooled and compared with results from an Eastern Cooperative Oncology Group (ECOG) study in which patients were treated with conventional chemotherapy. A series of adjustments were made to the ECOG sample to account for selection factors that restrict access of patients to transplantation. The transplant sample exhibits considerably higher disease-free survival when compared to the adjusted ECOG series (53% versus 21% at three years). The transplant series is somewhat younger than the ECOG series (median, 24 years versus 28 years). The impact of age on the disease-free survival results is difficult to assess because of the relatively small samples in the different age groups. However, by defining a suitable control group, methodology for making a critical comparison between the two modalities is presented which, if applied to larger samples of patients, should help to resolve the issue. In the absence of data from a large, prospective randomized study, a critical retrospective comparison of available data is essential in the assessment of treatment options.

Full dose versus attenuated dose daunorubicin, cytosine arabinoside, and 6-thioguanine in the treatment of acute nonlymphocytic leukemia in the elderly.

Between July 1, 1981 and November 1, 1982, 45 patients with acute nonlymphocytic leukemia (age, greater than or equal to 70 years) were randomly assigned to receive induction chemotherapy using either daunorubicin, cytosine arabinoside, and 6-thioguanine in full dosage (F DAT) or an attenuated schedule of the same drugs (At DAT) as part of an Eastern Cooperative Oncology Group controlled trial. Forty patients were deemed evaluable, 20 on each arm. The overall complete remission (CR) rate for all patients in both arms was 28% (11/40). There was no significant difference in CR rates between the two arms. There were 12 early deaths (less than 60 days) in the F DAT arm compared with only five early deaths on the At DAT arm (P = .05). Due primarily to this early death rate, the median survival for the F DAT group was 29 days v 159 days for the At DAT groups (P = .02). The range of survival of the patients in CR for the At DAT group given either one or two cycles of induction therapy was 121 to 414 days, while the survival range for the F DAT CR patients was 121-186 + days. The median survival for those not achieving CR was 14 days for the F DAT group v 80 days for the At DAT (P less than .02). Fifty-nine percent of the At DAT patients spent greater than 100 days out of the hospital v 12% for the F DAT group. Attenuated chemotherapy with lower doses of DAT is the preferred induction regimen for elderly patients with acute nonlymphocytic leukemia since it causes fewer early deaths, allows a better quality of life, and yields survival times as durable as intensive therapy.

Who gets adjuvant treatment for stage II and III rectal cancer? Insight from surveillance, epidemiology, and end results--Medicare.

PURPOSE: To examine the relationship between patient characteristics and the use of adjuvant pelvic radiation with and without chemotherapy among patients aged 65 years and older with stage II and III rectal cancer. PATIENTS AND METHODS: A retrospective cohort study using the Surveillance, Epidemiology, and End Results-Medicare linked database identified 1,411 patients aged 65 and older with resected stage II and III rectal cancers diagnosed between 1992 and 1996. From claims submitted to Medicare, we measured the use of pelvic radiation therapy with or without chemotherapy and pre- or postoperatively. RESULTS: Fifty-seven percent of patients received radiation, 42% received chemotherapy and radiation, and 7% had treatment delivered preoperatively. Age was the strongest determinant of treatment: 73% of patients aged 65 to 69, 66% aged 70 to 75, 52% aged 75 to 79, 39% aged 80 to 84, and 21% aged 85 to 89 received radiation. The age trend remained strong after adjusting for other factors that predict receipt of treatment and after exclusion of patients with any evident comorbidity (P <.001). Patients were more likely to receive radiation treatment if they had an abdominal perineal resection, stage III disease, or a T4 tumor. CONCLUSION: Because pelvic recurrences are a substantial cause of morbidity, further efforts are needed to ensure that elderly patients have the opportunity to make informed decisions regarding adjuvant treatment.

High-dose ifosfamide with mesna uroprotection: a phase I study.

Phase II trials of ifosfamide have been performed with standard doses of 5 to 8 g/m2/course. In this phase I study, 29 patients were treated with a 4-day continuous infusion ifosfamide to determine the maximum-tolerated dose and the nonhematologic dose-limiting toxicity. Autologous bone marrow support was to have been used for the subsequent dose level if granulocytes were more than 500/microL for more than 14 days in two of two to five patients at a given dose level. Doses were escalated from 8 to 18 g/m2 ifosfamide. Mesna was given at an equivalent dose by continuous infusion for 5 days. At the 18 g/m2 dose level, dose-limiting renal insufficiency and a median of 11 days (range, 8 to 18 days) of granulocytopenia (less than 500/microL) were observed. Thus, autologous bone marrow reinfusion ws not used. The duration of myelosuppression, the frequency and severity of mucositis, and renal tubular acidosis were all dose-dependent. Mild to moderate CNS toxicity also appeared to be related to dose; however, severe CNS toxicity (transient confusion, hallucinations, and somnolence) was observed sporadically at both low- and high-dose levels. Transient hematuria (greater than 50 red blood cells [RBCs]/high power field) occurred once but did not affect treatment. There were nine responses (two complete) in 27 heavily pretreated assessable patients including seven responses in 20 patients with advanced refractory sarcoma. Ifosfamide with mesna uroprotection can undergo considerable dose escalation over the usual prescribed doses before nonhematologic dose-limiting toxicity is encountered. Ifosfamide has broad cytotoxicity against solid tumors and may prove to be an important addition to high-dose combination chemotherapy regimens.

Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma.

PURPOSE: Several single-institution phase II trials have reported that the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) can induce major tumor responses in 40% to 50% of stage IV melanoma patients. This study was designed to compare the overall survival time, rate of objective tumor response, and toxicity of the Dartmouth regimen with standard dacarbazine treatment in stage IV melanoma patients. PATIENTS AND METHODS: In this multicenter phase III trial, 240 patients with measurable stage IV melanoma were randomized to receive the Dartmouth regimen (dacarbazine 220 mg/m(2) and cisplatin 25 mg/m(2) days 1 to 3, carmustine 150 mg/m(2) day 1 every other cycle, and tamoxifen 10 mg orally bid) or dacarbazine 1, 000 mg/m(2). Treatment was repeated every 3 weeks. Patients were observed for tumor response, survival time, and toxicity. RESULTS: Median survival time from randomization was 7 months; 25% of the patients survived > or = 1 year. There was no difference in survival time between the two treatment arms when analyzed on an intent-to-treat basis or when only the 231 patients who were both eligible and had received treatment were considered. Tumor response was assessable in 226 patients. The response rate to dacarbazine was 10.2% compared with 18.5% for the Dartmouth regimen (P =.09). Bone marrow suppression, nausea/vomiting, and fatigue were significantly more common in the Dartmouth arm. CONCLUSION: There was no difference in survival time and only a small, statistically nonsignificant increase in tumor response for stage IV melanoma patients treated with the Dartmouth regimen compared with dacarbazine. Dacarbazine remains the reference standard treatment for stage IV melanoma.

A note on the estimation of relative risks of rare genetic susceptibility markers.

The comparison of an incident case series with an incident series of second primary cancers, using either a case-control or follow-up study design, is proposed as an efficient method for evaluating the relative risk of a rare genetic susceptibility marker and its prevalence in the population, and for evaluating gene-environment interactions. The relative efficiency of this design versus a conventional case-control study is highly dependent on the population prevalence of the marker and its relative risk. However, for relatively rare but highly penetrant genes, the relative efficiency can be very high. In an example presented regarding a planned study of the p16 gene and its role in melanoma, a conventional case-control study may require up to 70 times as many subjects to achieve equivalent precision to the study of second primaries. The use of second primary cancers in this way requires assumptions about the validity of the classification of a new tumor as a second primary, the extent to which risk of a second cancer is influenced by treatment of the first cancer, and the nature and extent of surveillance bias. However, the problems of ascertaining a valid series of population controls are avoided. The study of second cancers represents an important and underused tool in molecular and genetic epidemiology.

Statistical analysis of molecular epidemiology studies employing case-series.

The case-series design is being used increasingly to explore associations between environmental risk factors and genetic markers. It is demonstrated that the odds ratio derived from a case-series study is the ratio of the relative risk for developing marker-positive disease to the relative risk for developing marker-negative disease. This parameter is an empirical manifestation of etiological heterogeneity with respect to the risk factor under study, and it can be used to construct a statistical significance test. Presence of etiological heterogeneity, as reflected in departures of this parameter from unity, could be a result of either the presence of distinct causal mechanisms for the two categories of cases, or a different strength of effect via the same mechanism. The case-series approach represents an efficient and valid approach for evaluating gene-environment associations, especially in referral centers where it is difficult to identify a valid control group.

The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations.

Several studies using families with multiple occurrences of breast cancer have provided evidence for a very high lifetime penetrance in carriers of BRCA1 or BRCA2 mutations. However, there are reasons to suspect that the estimates of penetrance from studies of cancer families may be inflated. Access to the genotypes of incident cases of breast cancer in three hospitals and from a large series of unaffected survey participants provided the basis for direct estimation of the age-specific relative risks attributable to these mutations, and the resulting lifetime penetrance, without any reference to familial aggregation of cancer. Cases were identified from incident series of Jewish patients treated for primary breast cancer at the three hospitals. Control data were obtained from the large series of Jewish women recruited in the Washington, D.C., area by investigators at the National Cancer Institute and limited to 3434 women with no previous history of breast or ovarian cancer. All subjects were genotyped for the three mutations that are relatively common in Ashkenazi Jews, namely 185delAG and 5382 insC in BRCA1 and 6174delT in BRCA2. For BRCA1, the relative risks of breast cancer were estimated to be 21.6 in women under 40 years of age, 9.6 in women 40-49 years of age, and 7.6 in women > or = 50 years of age. On the basis of these estimates, the penetrance of breast cancer at age 70 among BRCA1 mutation carriers is estimated to be 46% (95% confidence, 31%-80%) rising to 59% (95% confidence, 40%-93%) at age 80. For BRCA2, the relative risks in the same three age categories were estimated to be 3.3, 3.3, and 4.6, respectively, resulting in a penetrance at age 70 of 26% (95% confidence, 14%-50%) rising to 38% (95% confidence, 20%-68%) at age 80. The lifetime risk of breast cancer in Jewish women who are mutation carriers estimated via this approach is substantially lower than the reported lifetime risks estimated using multiple-case families. The risks appear to be different for carriers of BRCA1 and BRCA2 mutations.

Methodological issues in studies of the treatment, diagnosis, and etiology of prostate cancer.

Clinical and epidemiological research on prostate cancer is faced with some unusual methodological challenges. The very high prevalence of latent cancer, much of which never becomes clinically manifest, complicates the approach to screening and the conduct of epidemiological studies. Cost-effectiveness issues are especially relevant regarding screening policies, and these trade-offs are complicated by the absence of definitive results on the effectiveness of the various treatment options. The presentation of advanced disease is also unusual, in that the vast majority of patients do not have measurable disease suitable for traditional studies of new chemotherapy agents. These problems necessitate creative approaches to the design and analysis of research studies in this disease: cost-effectiveness analysis is crucial to the evaluation of screening policies; opportunistic designs will be essential to the valid study of cancer etiology, eg, the use of cystoprostatectomy series for studies of epidemiologic risk factors; and posttreatment changes in PSA levels may be valuable as a criterion for screening new agents in advanced disease. Regardless of these new methods, traditional methodological approaches are essential to the valid study of prostate cancer. Randomization is required for valid comparison of treatments and screening strategies. Statistical analysis should observe the intent-to-treat principle whereby patient groups are analyzed with respect to the planned, rather than the delivered therapy, and studies should have sufficiently large sample sizes to reliably distinguish the true effects of the interventions from random statistical fluctuation. Recently, meta-analysis has become popular as a tool for synthesizing the information from available studies on a specific clinical problem. Its most conspicuous success has been in showing the efficacy of adjuvant therapy in breast cancer, for which many individual studies appeared to give conflicting results.64 In this setting there was a large number of published randomized trials, many of which had large sample sizes and long follow-up, and so the meta-analysis was able to show convincingly a small but clinically meaningful treatment effect on long-term disease recurrence and survival. This is similar to the situation in localized prostate cancer in all respects except for the availability of randomized trials. Unfortunately there is no free lunch. This technique can only be applied if the high quality data are available. One must be similarly cautious in applying decision analytic techniques (and also cost-effectiveness analysis) to try to resolve clinical dilemmas.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of local control on metastatic dissemination in carcinoma of the prostate: long-term results in patients treated with 125I implantation.

The study evaluates the effect of the locally recurring tumor on the incidence of metastatic disease in early stage carcinoma of the prostate. The probability of distant metastases was studied in 679 patients with Stage B-C/N0 carcinoma of the prostate treated at MSKCC between 1970 and 1985 (median follow-up of 97 months). Patients were staged with pelvic lymph node dissection and treated with retropubic 125I implantation. The actuarial distant metastases free survival (DMFS) for patients at risk at 15 years after initial therapy was 37%. Cox proportional hazard regression analysis of covariates affecting the metastatic outcome showed that local failure, used in the model as a time dependent variable, was the most significant covariate, although stage, grade, and implant volume were also found to be independent variables. The relative risk of metastatic spread subsequent to local failure was 4-fold increased compared to the risk without evidence of local relapse. The 15-year actuarial DMFS in 351 patients with local control was 77% compared to 24% in 328 patients who developed local relapses (p less than 0.00001). The relation of distant spread to the local outcome was observed regardless of stage, grade, or implant dose. Even stage B1/N0-Grade I patient with local control showed a 15-year actuarial DMFS of 82%, compared to 22% in patients with local relapse; p less than 0.00001). The median local relapse-free survival (LRFS) in the 268 patients with local recurrences who did not receive hormonal therapy before distant metastases were detected was 51 months, compared to a median of 71 months for DMFS in the same patients (p less than 0.001), consistent with the possibility that distant dissemination may develop secondary to local failure. Furthermore, distant metastases in patients with local control, apparently already existing as micrometastases before treatment, were detected earlier (median DMFS of 37 months) than in patients with local relapse (median DMFS of 54 months; p = 0.009). These data suggest that the existence and re-growth of local residual disease in localized prostatic carcinoma promotes an enhanced spread of metastatic disease, and that early and complete eradication of the primary tumor is required if a long term cure is to be achieved, although the clinical expression of secondary metastases may not become apparent for 6.5 years or more in one-half of the patients.

Root-induced iron oxidation and pH changes in the lowland rice rhizosphere.

Measurements of profiles of ferrous and ferric iron and pH in blocks of reduced soil in contact with planar layers of rice (Oryza sativa L.) roots are reported. Initially 11-d-old plants were kept in contact with the soil for up to 12 d. Over this period, substantial quantities of iron were transferred towards the root plane, producing a well-defined zone of ferric hydroxide accumulation. The pH in this zone fell by more than two units. The profiles changed with time. The decrease in pH was in part due to protons generated in ferrous iron oxidation, and in part due to protons released from the roots to balance excess intake of cations over anions, N being taken up chiefly as NH4 + . But the decrease in pH was less than expected from the net acid production in these two processes, possibly because of proton consumption in CO2 uptake by the roots. Because of the pH-dependence of soil acidity diffusion, the two sources of acidity greatly reinforce each other. Some implications for nutrient and toxin dynamics are discussed.