MicroRNA-224 is associated with colorectal cancer progression and response to 5-fluorouracil-based chemotherapy by KRAS-dependent and -independent mechanisms.

BACKGROUND: Colorectal cancers arise from benign adenomas, although not all adenomas progress to cancer and there are marked interpatient differences in disease progression. We have previously associated KRAS mutations with disease progression and reduced survival in colorectal cancer patients. METHODS: We used TaqMan low-density array (TLDA) qRT-PCR analysis to identify miRNAs differentially expressed in normal colorectal mucosa, adenomas and cancers and in isogeneic KRAS WT and mutant HCT116 cells, and used a variety of phenotypic assays to assess the influence of miRNA expression on KRAS activity, chemosensitivity, proliferation and invasion. RESULTS: MicroRNA-224 was differentially expressed in dysplastic colorectal disease and in isogeneic KRAS WT and mutant HCT116 cells. Antagomir-mediated miR-224 silencing in HCT116 KRAS WT cells phenocopied KRAS mutation, increased KRAS activity and ERK and AKT phosphorylation. 5-FU chemosensitivity was significantly increased in miR-224 knockdown cells, and in NIH3T3 cells expressing KRAS and BRAF mutant proteins. Bioinformatics analysis of predicted miR-224 target genes predicted altered cell proliferation, invasion and epithelial-mesenchymal transition (EMT) phenotypes that were experimentally confirmed in miR-224 knockdown cells. CONCLUSIONS: We describe a novel mechanism of KRAS regulation, and highlight the clinical utility of colorectal cancer-specific miRNAs as disease progression or clinical response biomarkers.

What is a virtual multidisciplinary team (vMDT)?

BACKGROUND: Multidisciplinary team meetings (MDTs), also known as tumour boards or multidisciplinary case conferences, are an integral component of contemporary cancer care. There are logistical problems with setting up and maintaining participation in these meetings. An ill-defined concept, the virtual MDT (vMDT), has arisen in response to these difficulties. We have, in order to provide clarity and to generate discussion, attempted to define the concept of the vMDT, outline its advantages and disadvantages, and consider some of the practical aspects involved in setting up a virtual MDT. METHODS: This is an unstructured review of published evidence and personal experience relating to virtual teams in general, and to MDTs in particular. RESULTS: We have devised a simple taxonomy for MDTs, discussed some of the practicalities involved in setting up a vMDT, and described some of the potential advantages and disadvantages associated with vMDTs. CONCLUSION: The vMDT may be useful for discussions concerning rare or unusual tumours, or for helping guide the assessment and management of patients with uncommon complications related to treatment. However, the vMDT is a niche concept and is currently unlikely to replace the more traditional face-to-face MDT in the management of common tumours at specific sites.

Characteristics of patients dying within 30 days of diagnosis of breast or colorectal cancer in Scotland, 2003-2007.

BACKGROUND: Recent research has shown that most of the excess risk of death following breast and colorectal cancer in England compared with Norway and Sweden occurs in older age groups during the first year, and especially in the first month of follow-up. The aim of this study was to explore the characteristics of patients dying within 30 days of being diagnosed with one of these cancers in Scotland during 2003-2007. METHODS: Anonymised cancer registry records linked to hospital discharge and death records were extracted. The study population was divided into patients who died within 30 days of diagnosis (cases) and those who survived beyond this threshold (controls). Differences in patient-, tumour-, and health service-related characteristics were assessed using the χ(2)-test and logistic regression. RESULTS: Patients dying within 30 days were more likely to be elderly and to have experienced emergency admission to non-surgical specialities. Their tumours were less likely to have been verified microscopically, but they appeared more likely to be of high grade and advanced in stage. A substantial number of patients died from causes other than their cancer. CONCLUSION: These results suggest that early mortality after a diagnosis of breast or colorectal cancer may be partly due to comorbidity and lifestyle factors, as well as due to more advanced disease. Further research is required to determine the precise explanation for these findings and, in particular, if any potentially avoidable factors such as delays in presentation, referral, or diagnosis exist.

Cooperation across the histocompatibility barrier: H2d T cells primed to antigen in an H-2d environment can cooperate with H-2k B cells.

H-2d spleen cells derived from either tetraparental or semiallogeneic radiation bone marrow chimeras can be primed to antigen within H-2d recipients to generate helper T cells capable of cooperating in a secondary response with equal efficiency with H-2d or H-2k B cells. Thus it would seem that the cooperative act between T and B cells does not require that the T cell interacts with its target B cells by either cell interaction genes or via an altered self mechanism involving both antigen and the target B-cell I-region products. This does not preclude a requirement for associative recognition or altered self in the interaction of helper T cells with accessory cells.

Antigen-specific T-cell factor in cell cooperation: physical properties and mapping in the left-hand (K) half of H-2.

Mouse thymus cells, educated to poly(tyrosyl,glutamyl)-polyDLalanyl--polylysyl [(T,G)-A--L], release an antigen-specific factor on brief culture in vitro. The factor cooperates with bone marrow cells in the antibody response to (T,G)-A--L in irradiated recipients. Its mol wt determined from Sephadex G100 chromatography is in the region of 50,000. The factor is removed by specific antigen-coated columns, but not by anti-immunoglobulin (anti-Fab, anti-micro, anti-Fv) adsorbents. The factor is removed by alloantisera directed against the H-2 haplotype of the strain in which it is produced. Moreover, only antisera with specificity for the K side of H-2 were successful in removing the factor activity.

Antigen-specific T-cell factor in cell cooperation. Mapping within the I region of the H-2 complex and ability to cooperate across allogeneic barriers.

Further mapping of the mouse T-cell factor specific for poly(Try,Glu)-polyD-LAla--polyLys is reported. It is shown to be a product of the I-A subregion of the H-2 complex by the use of antisera either raised specifically against or made specific, by absorption, for different regions of the H-2 complex. The factor cooperates across allogeneic barriers, e.g., when factor produced by one strian is combined with bone marrow cells of other H-2 incompatible strains.

Suspected malignant cord compression - improving time to diagnosis via a 'hotline': a prospective audit.

The aim of the study was to achieve earlier diagnosis of malignant cord compression (MCC) using urgent magnetic resonance imaging (MRI) for selected patients. A comparison was carried out of the current prospective audit of 100 patients referred by a general practitioner or a consultant over 32 months with both a previous national Clinical Research and Audit Group (CRAG) prospective audit (324 cases of MCC) and an earlier retrospective audit of 104 patients referred with suspected MCC. A telephone hotline rapid-referral process for patients with known malignancy and new symptoms (severe nerve root pain +/- severe back pain) was designed. Patients were considered for urgent MRI after discussion with a senior clinician responsible for the hotline. Appropriate referrals were discussed with radiology and oncology ensuring timely MRI reporting and intervention. The main outcome measures are as follows: time from referral to diagnosis; time from the onset of symptoms to diagnosis; and mobility at diagnosis. A total of 50 patients (52%) of those scanned had either MCC (44) or malignant nerve root compression (6) compared with the earlier rate of 23 out of 104 patients (22%). Ten out of 44 MCC patients (23%) were paralysed at diagnosis, compared with 149 out of 324 (46%) in the CRAG audit. Time from reporting pain to diagnosis was 32 days compared with 89 days in the CRAG audit. Median time from referral to diagnosis was 1 day, again considerably shorter than the CRAG audit time of 15 days (interquartile (IQ) range: 3-66). In patients at risk of MCC, fast-track referral with rapid access to MRI reduces time between symptom onset and diagnosis, improves mobility at diagnosis and reduces the number of negative MRI scans.

Paper versus electronic feedback in high stakes assessment.

Tablet computers have emerged as increasingly useful tools in medical education, particularly for assessment. However, it is not fully established whether tablet computers influence the quality and/or quantity of feedback provided in high stakes assessments. It is also unclear how electronically-recorded feedback relates to student performance. Our primary aim was to determine whether differences existed in feedback depending on the tool used to record it. METHODS: We compared quantitative and qualitative feedback between paper-scoring sheets versus iPads™ across two consecutive years of a final year MBChB (UK medical degree) Objective Structured Clinical Examination. Quality of comments (using a validated five-point rating scale), number of examiner comments and number of words were compared across both methods of recording assessment performance using chi-squared analysis and independent t-test. We also explored relationships between student performance (checklist and global scoring) and feedback. RESULTS: Data from 190 students (2850 paper scored interactions) in 2015 and 193 (2895 iPad™ scored interactions) in 2016 were analysed. Overall, a greater number of comments were given with iPad™ compared to written (42% versus 20%; p < 0.001) but the quality of feedback did not differ significantly. For both written and electronic feedback, students with low global scores were more likely to receive comments (p < 0.001). CONCLUSION: The use of iPads™ in high stakes assessment increases the quantity of feedback compared to traditional paper scoring sheets. The quantity and quality of feedback for poorer performing candidates (by global score) were also better with iPad™ feedback.

Smoking compromises cause-specific survival in patients with operable colorectal cancer.

AIMS: To assess whether active smoking compromises survival in patients with colorectal cancer. MATERIALS AND METHODS: We studied a regionally based cohort of 284 consecutive patients referred to the Tayside Cancer Centre for consideration of adjuvant treatment after curative surgery for colorectal cancer. RESULTS: Cause-specific survival was significantly worse (P = 0.0015) in patients who were actively smoking at the time of their first post-operative visit. The absolute difference in 5-year cause-specific survival (active smokers vs the rest) was 21%. In adjusted multi-variate analysis of patients after pathologically complete (R0) resection, the hazard ratio was 2.55 (95% confidence interval 1.40-4.64) in active smokers compared with non-smokers. T stage, number of positive nodes and co-morbidity score were also of independent prognostic influence. CONCLUSIONS: Persistent smoking was, in this small series, an important and independent predictor of cancer-related death after surgery for cancer of the large bowel. Because smoking and deprivation are related, some of the adverse effects of deprivation upon survival in this group of patients may be explained by smoking behaviour.

Bone metastases: pathophysiology and management policy.

The pathophysiology and options for management of bone metastases as well as criteria for determining response to therapy are reviewed. Bone metastases are frequently one of the first signs of disseminated disease in cancer patients. In the majority of patients, the primary tumor is in the breast, prostate, or lungs. Although almost all patients will die of their disease, a proportion of the patients will survive for several years. Treatment is primarily palliative: the intention is to relieve pain, prevent fractures, maintain activity and mobility, and, if possible, to prolong survival. Therapeutic options include local treatment with radiotherapy and/or surgery, and systemic treatment using chemotherapy, endocrine therapy, radioisotopes, agents such as diphosphonates, which inhibit resorption of bone, as well as analgesic and antiinflammatory drugs. The mechanisms by which pain is relieved by several of these therapies remain unclear but actions beyond a simple tumoricidal effect appear to be important. There have been few randomized trials comparing the therapeutic options, and the criteria for assessing response to therapy have, in general, been poorly defined. There is a need for rigorous clinical investigations that assess the efficacy of the various therapeutic possibilities by using well-defined and validated criteria of response.

Antibody-guided irradiation of advanced ovarian cancer with intraperitoneally administered radiolabeled monoclonal antibodies.

Twenty-four patients with persistent epithelial ovarian cancer after chemotherapy with or without external beam irradiation, were treated with intraperitoneally administered 131I-labeled monoclonal antibodies HMFG1, HMFG2, AUA1, H17E2, directed against tumor-associated antigens. Acute side effects were mild abdominal pain, pyrexia, diarrhea, and moderate reversible pancytopenia. One patient developed a subphrenic abscess requiring surgical drainage. Eight patients with large volume disease, ie, greater than 2 cm tumor diameter, did not respond to antibody-guided irradiation and died of progressive disease within 9 months of treatment. Sixteen patients had small-volume (less than 2 cm) disease at the time of treatment with radiolabeled antibody. Seven patients failed to respond, and of nine initial responders, four patients remain alive and free from disease 6 months to 3 years from treatment. Analysis of the data on relapse indicated that doses greater than 140 mCi were more effective than lower doses. We conclude that the intraperitoneal administration of 140 mCi or more of 131I-labeled tumor-associated monoclonal antibodies represents a new and potentially effective form of therapy for patients with small-volume stage III ovarian cancer.

Chinese medical herbs for chemotherapy side effects in colorectal cancer patients.

BACKGROUND: Side effects, including nausea and vomiting, sore mouth , diarrhoea, hepatotoxicity, myelosuppression, and immunosuppression , are commonly encountered in patients with colorectal cancer who are treated with chemotherapy. A variety of Chinese herbal medicines have been used for managing these adverse effects. OBJECTIVES: To assess the effect of herbal medicines plus chemotherapy, compared with chemotherapy alone, on the side effects of chemotherapy on the quality of life, and on adverse events in patients with colorectal cancer. SEARCH STRATEGY: We searched the Cochrane Library, MEDLINE, EMBASE, CBM, and handsearched the relevant Chinese journals. SELECTION CRITERIA: Randomised trials comparing either chemotherapy only or chemotherapy plus anti-emetics (tropisetron, sulpiride etc) with chemotherapy plus Chinese herbs. DATA COLLECTION AND ANALYSIS: Trial quality was assessed independently by two reviewers. Data were extracted by one reviewer and checked by the second reviewer. Since the four included studies differed significantly in design, we could only perform limited meta-analyses. We have therefore presented the majority of the data in narrative form. MAIN RESULTS: We included four relevant trials. All of them were of low quality. All of studies used a decoction containing Huangqi compounds as the intervention with chemotherapy. The intervention groups of three studies were compared to a chemotherapy alone control group, the fourth study compared the decoction of Huangqi compounds with two other Chinese herbal interventions. None of the studies reported on primary outcome using Common Toxicity Criteria (CTC). There was a significant reduction in the proportion of patients who experienced nausea & vomiting when decoctions of Huangqi compounds were given in addition to chemotherapy. There was also a decrease in the rate of leucopenia (WBC <3 x 10(9) per L). Huangqi compounds were also associated with increases in the proportions of T-lymphocyte subsets: CD3; CD4 and CD8. Huangqi decoctions had no significant effects on Immunoglobulins G, A or M. AUTHORS' CONCLUSIONS: Despite the included studies being of low quality, the results suggest that decoctions of Huangqi compounds may stimulate immunocompetent cells and decrease side effects in patients treated with chemotherapy. Due to the methodological limitations of the studies, there is no robust demonstration of benefit. We found no evidence of harm arising from the use of Chinese herbs. We need high quality randomised controlled studies investigating the effects of decoctions of Chinese herbs, particularly Astragalus spp.(as in Huangqi), upon chemotherapy-related side effects.

Anti-CD45 and anti-CD52 (Campath) monoclonal antibodies effectively eliminate systematically disseminated human non-Hodgkin's lymphoma B cells in Scid mice.

Severe combined immunodeficient (Scid) mice inoculated with the human (t(14;18)-positive B cell lines DoHH2 and BEVA develop lethal systemically disseminated lymphoma (de Kroon et al., Leukemia 8:1385, and Blood 80 [suppl 1]:436). These models were used to study the therapeutic effect of rat-anti-human CD52 (Campath-1G) or CD45 monoclonal antibodies (mAbs) on systemically disseminated tumor cells and on tumor cells present in solid tumor masses. Both mAbs were effective in inhibiting growth of systemically disseminated malignant cells. When treatment with anti-CD52 or anti-CD45 mAbs at a dose of 30 micrograms/mouse/d for 4 days was started 24 hours after intravenous inoculation of human DoHH2 or BEVA cells, a 3-log kill of tumor cells was observed as measured by prolonged survival. After treatment, surviving animals injected with high numbers of BEVA cells showed tumor masses in liver, kidney, and mesenteric lymph nodes. In contrast to nontreated animals, however, only low numbers of malignant cells were found in peripheral blood, and bone marrow was free of tumor cells. Similarly, after mAb treatment of mice inoculated subcutaneously (sc) with DoHH2 cells, no tumor cells could be found in the bone marrow, and few DoHH2 cells could be detected in the peripheral blood, spleen, liver, kidney, or lung. In contrast, tumor cells present in subcutaneous tumors and axillary lymph nodes were relatively unaffected by mAb therapy. The presence of rat immunoglobulin (Ig) could be demonstrated on surviving tumor cells. The presence of murine macrophages in areas in these tumors that were depleted of DoHH2 cells suggested that the mAb-mediated antitumor effect observed in the Scid mouse model is mediated by cellular mechanisms. Apparently these mechanisms were not sufficient to eliminate the fast-growing tumor cells present in the protected sites. Our results indicate that treatment with anti-CD52 or anti-CD45 mAbs potentially may be useful as adjuvant immunotherapy for systemically disseminated B cell lymphoma.

Kaposi's sarcoma in HIV infection treated with vincristine and bleomycin.

OBJECTIVE: To evaluate the efficacy and toxicity of vincristine and bleomycin when used in combination to treat patients with progressive Kaposi's sarcoma. DESIGN: A retrospective case notes review. SETTING: The departments of Immunology and Genito-Urinary Medicine, St Mary's Hospital, London, UK. PATIENTS: All patients presenting with progressive Kaposi's sarcoma and requiring chemotherapy between January 1987 and January 1990, who had received no previous systemic chemotherapy. INTERVENTIONS: Treatment with vincristine (2 mg) and bleomycin (30 mg, 18 h infusion), or vinblastine (2.5-5.0 mg) if peripheral neuropathy developed. Treatment with zidovudine and prophylaxis of opportunistic infections where indicated. OUTCOME MEASURES: Response, toxicity and survival. RESULTS: Overall, patients had a poor prognosis: 33 out of 46 (72%) had had a previous opportunistic infection, had a mean CD4 count of 144 x 10(6) (20 out of 46 tested) and a mean Karnofsky index of 75.4. They received a median of five cycles of therapy: a partial response was achieved in twenty-six patients (57%), disease progression was halted in a further 16 (35%), while disease progression continued in four (9%) despite therapy; there were no complete responders. Mean duration of response was 2 months (s.d., 1.26 months), survival was 8 months (s.d., 6.7 months) from start of therapy and 17 months (s.d., 8.9. months) from first AIDS diagnosis. On multivariate analysis the best predictor of mortality was the presence of previous opportunistic infection (P = 0.00653). Side-effects were minimal in comparison with other studies. The most common side-effect, in 13 cases (28%), was peripheral neuropathy, which may in part represent the prevalence of HIV neuropathy or remain as background. Haematological toxicity was uncommon. CONCLUSIONS: Treatment for HIV-related Kaposi's sarcoma in advanced HIV disease is becoming more necessary as disease profiles change. Conventional chemotherapy regimens for malignancy are not well tolerated in these patients and may not be indicated. This regimen is effective and has low toxicity in AIDS patients. Non-responders should be considered for more intensive regimens.

Is placental alkaline phosphatase (PLAP) a useful marker for seminoma?

The usefulness of placental alkaline phosphatase (PLAP) as a tumour marker was assessed in 1578 serum samples from 236 patients with seminoma. Smoking habits were known for all but 7 patients (22 samples). Smoking was associated with significantly higher mean levels of PLAP in disease-free patients (28.8 [S.E. 2.1] U/l vs. 15.9 [1.3] U/l in non-smokers). Mean PLAP levels were higher in patients with active disease (78.6 [23.5] U/l in non-smokers and 47.2 [18.5] U/l in smokers). The median values showed a similar trend. However, there was considerable overlap between the various groups and differences between mean and median values indicated that PLAP values were distributed asymmetrically. The predictive value of PLAP as a tumour marker was consequently much less than superficial inspection of these values might suggest. In 97 patients on surveillance, only 2 out of 11 patients who relapsed had elevated PLAP at the time of clinically detectable relapse. With the upper limit of normal PLAP quoted by our laboratory (35 U/l), specificity and sensitivity were, respectively, 88% and 45% (all patients) and 96% and 47% (non-smokers). The sensitivity and specificity of PLAP were assessed in more detail for a series of threshold values (normal vs. abnormal) with a graphical method. Only in non-smokers did PLAP seem useful and even in this group the positive predictive value of an "abnormal" test may be low; less than 50% in clinically relevant circumstances. Serum PLAP assay cannot usefully stand alone as a marker for seminoma and its routine estimation contributes little to follow-up.

The detection of alloantibodies to subpopulations of human lymphocytes: an adaptation of the indirect anti-immunoglobulin rosetting reaction (IARR).

An indirect anti-immunoglobulin rosetting reaction (IARR) can be successfully used to detect alloantibodies to human lymphocytes. In this paper we describe an adaptation of the IARR which allows detection of alloantibodies to human lymphocyte subpopulations. Fluorescein labelled sheep red cells, as a T cell marker, are incorporated into the rosetting reactions and by looking for rosettes with two indicator cell types, sheep and ox, one can determine if the alloantibodies are reacting with T cells or non-T cells. This type of assay is more sensitive than a standard cytotoxic test and can detect non-cytotoxic antibodies. The results show that this rosetting assay with two types of indicator cell can be useful in the study of pregnancy anisera, particularly those that are thought to contain reactivity directed solely against non-T cells. These antisera probably recognise the human DR antigens which are thought to be equivalent to the rodent Ia antigens.

An indirect anti-immunoglobulin rosetting reaction to detect alloantibodies to human lymphocytes.

A test is reported which detects alloantibody, absorbed onto the surface of human lymphocytes from multiparous antisera, by means of a red cell rosette assay. The red cells, trypsinised ox, are coupled with anti-immunoglobulin using chromic chloride. The antiglobulin used is rabbit anti-human IgG (Fc), chosen to avoid reaction with the surface immunoglobulin naturally present on human B lymphocytes. The reaction is termed the Indirect Anti-immunoglobulin Rosetting Reaction (IARR). The IARR is shown to be specific in the following ways: anti-immunoglobulin coupled ox cells do not react with normal human lymphocytes nor with lymphocytes treated with non-reactive serum. Red cells coupled with normal rabbit IgG do not react with normal or alloantibody coated lymphocytes. Multiparous sera (reactive with other individuals) do not react with cells of the serum donor in the IARR. Finally, the coupled red cells do not usually react with lymphocytes which have absorbed immune complexes onto their Fc receptors. The IARR is shown to be more sensitive than a standard cytotoxic test for detection of alloantibody. Several possible applications of the IARR are discussed.

Carcinoma of the prostate: results of radical radiotherapy (1970-1985).

PURPOSE: To determine the outcome and prognostic factors in patients with localized carcinoma of the prostate treated with external beam radiation therapy. METHODS AND MATERIALS: A retrospective review of 999 patients with histologically confirmed adenocarcinoma of the prostate treated radically with megavoltage irradiation at the Princess Margaret Hospital between 1970 and 1985. Prognostic factors were analyzed using recursive partitioning method. RESULTS: Overall survival at 5 and 10 years were 69.8% and 40.1% for the whole group. The cause-specific survival rates were 78.9% and 53.5%, respectively. The cause-specific survival rates were significantly different at 10 years by T stage, T1 being 79.0%, T2 66.0%, T3 55% and T4 22%. The overall clinical local control rates was 77% in the first 5 years following treatment. There was no statistically significant difference in the local control rates of T1 and T2 stage disease at 5 years, the combined rate being 88%. Significant differences were observed between other stages, being 76% for T3 and 55% for T4. At 10 years the control rate for T1 tumours was maintained for T1 stage disease (92%) but was significantly reduced for other stages, T2 75%, T3 67% and for T4 37%. In the whole group 33.5% of patients had distant metastases in the first 5 years. The distant relapse rates at 10 years were significantly different by T stage, being 20% for T1, 33% for T2, 55% for T3 and 87% for T4. Multivariate analysis demonstrated that only T stage and histological grade were independent prognostic covariates for cause-specific survival. Age was the only other independent variate in terms of overall survival. The late radiation related morbidity was 2.3% overall; 1.3% affecting rectum and recto-sigmoid and 1.0% arising in the bladder. CONCLUSION: In terms of survival the results of radiotherapy of intracapsular disease were excellent, but they were less satisfactory in patients with direct extracapsular extension. The assessment of local control was difficult and may have reflected more the lack of local disease progression rather than true local tumor control. The treatment was well tolerated and there were few serious late complications.

Results of a policy of surveillance in stage I testicular seminoma.

PURPOSE: To determine what proportion of patients with Stage I testicular seminoma will be cured with orchidectomy alone. METHODS AND MATERIALS: From August 1984 to December 1991 148 patients with Stage I testicular seminoma were entered on a prospective study of surveillance following orchidectomy. The eligibility criteria included a normal chest X ray, lymphogram, computed tomography (CT) of the abdomen and pelvis, and normal post-orchidectomy tumor markers (AFP and BHCG). Patients were followed with a clinical assessment (markers, chest X ray and CT abdomen and pelvis) at 4 to 6 monthly intervals. RESULTS: With a median follow-up of 47 months (range 7-87 months), the actuarial relapse-free rate was 81% at 5 years. Twenty-three patients have relapsed with a median time to relapse of 15 months (range 2-61 months). Four patients (17%) relapsed at 4 or more years from diagnosis. Twenty-one of the 23 relapses occurred in the paraaortic lymph nodes, one patient relapsed in the mediastinum and ipsilateral inguinal nodes and one patient had an isolated ipsilateral inguinal node relapse. Nineteen patients were treated for relapse with external beam radiation therapy of which three developed a second relapse and were salvaged with chemotherapy. Four patients were treated for first relapse with chemotherapy and one developed a second relapse and died of disease. Age at diagnosis was the only prognostic factor for relapse, with patients age < or = 34 having an actuarial relapse-free rate at 5 years of 70% in contrast to a 91% relapse-free rate in those > 34 years of age. CONCLUSIONS: We recommend that surveillance in Stage I testicular seminoma should only be performed in a study setting until further data regarding the risk of late relapse and the efficacy of salvage chemotherapy is available.