Biomedical subjects
R T Oliver
Publications and source records attributed to R T Oliver.
Prediction of relapse after lymph node dissection for germ cell tumours: can salvage chemotherapy be avoided?
Salvage chemotherapy has been used by some oncology centres for patients with residual malignant or immature elements in retroperitoneal lymph node dissections removed for metastatic non-seminomatous germ cell tumours. However, surveillance of these patients shows that many are cured by surgery alone. 118 retroperitoneal lymph node dissections for metastatic non-seminomatous germ cell tumours were reviewed and the morphology seen within them was quantified. 28 of these had immature or malignant elements and had been treated by surveillance before administration of further chemotherapy. The proliferation rate in these cases was assessed by immunochemistry. The proliferation index and the amount of embryonal carcinoma (EC) were both predictors of recurrence and therefore the need for further chemotherapy. Patients with greater than 25% of EC had an 84% chance of relapse and those with a Ki-67 index of greater than 50% had a 71% chance of relapse. The two tests had a positive predictive value of 83% and 71%, respectively. Patients with such a high risk of recurrence could be considered for post-operative adjuvant therapy at this point whilst others would be suitable for a watchful waiting approach.
The use of multicolor fluorescence technologies in the characterization of prostate carcinoma cell lines: a comparison of multiplex fluorescence in situ hybridization and spectral karyotyping data.
Recent studies have identified several chromosome regions that are altered in primary prostate cancer and prostatic carcinoma cell lines. These targeted regions may harbor genes involved in tumor suppression. We used multiplex fluorescence in situ hybridization (M-FISH) to screen for genetic rearrangements in four prostate cancer cell lines, LNCaP, LNCaP.FCG, DU145, and PC3, and compared our results with those recently obtained using spectral karyotyping (SKY). A number of differences was noted between abnormalities characterized by SKY and M-FISH, suggesting variation in karyotype evolution and characterization by these two methodologies. M-FISH analysis showed that hormone-resistant cell lines (DU145 and PC3) contained many genetic alterations (> or =15 per cell), suggesting high levels of genetic instability in hormone-refractory prostate cancer. Most chromosome regions previously implicated in prostate cancer were altered in one or more of these cell lines. Several specific chromosome aberrations were also detected, including a del(4)(p14) and a del(6)(q21) in the hormone-insensitive cell lines, a t(1;15)(p?;q?) in LNCaP, LNCaP, and PC3, and a i(5p) in LNCaP.FCG, DU145, and PC3. These clonal chromosome abnormalities may pinpoint gene loci associated with prostate tumourigenesis, cancer progression, and hormone sensitivity.
Combination of HPLC and solid-phase binding assay for isolation and purification of MHC class I and associated peptides using a bladder tumour cell line.
The major histocompatibility complex (MHC) class I molecules present processed self and non-self peptides to T lymphocytes. Given that the class I peptide complex plays a critical role in cell-mediated immunity, it is important to identify the nature of class I-associated peptides unique to malignant cells as a prelude to the development of vaccines. The aim of this study was to combine immuno-bead purification (using anti-class I antibody W6/32) technique, sequential ultra-filtration and high performance liquid chromatography (HPLC) to isolate class I antigens and associated peptides from an in-house established bladder tumour cell line (Fen) whose missing class I antigens had been restored by beta2-microglobulin (beta2-m) gene transfaction. The results were as follows: (a) class I antigens could be separated from tumour cell lysate but only from the class I positive Fen cells; (b) treatment of CNBr-W6/32 beads pre-exposed to class I positive Fen lysate and eluted with dissociation agent (mild acid) resulted in the release of more than 20 peptides at an approximate molecular weight of between 700 and 3000 Da based on SDS-PAGE and silver staining analysis; (c) purified and eluted peptides from class I antigens showed distinct peaks when analysed by HPLC. The data presented in this investigation demonstrated the feasibility of isolating class I antigens and associated peptides from a bladder tumour cell line. The extension of these approaches to isolate peptides from tissue tumour biopsies may help the future of vaccine therapy in cancer patients.
Carboplatin AUC8 in combination with etoposide and bleomycin in the treatment of intermediate and poor-risk metastatic germ cell tumours: a phase II study.
PURPOSE: Carboplatin has demonstrated significantly poorer response rates in non-seminomatous germ cell tumours. A phase II study of higher than standard doses of carboplatin was conducted because of suspicion that the poorer response might have been due to suboptimal dosing. PATIENTS AND METHODS: A group of 19 patients with advanced germ cell tumours (International Germ Cell Cancer Collaborative Group intermediate and poor prognosis) were treated with carboplatin at an AUC of 8 mg/ml.min (using Calvert's formula) on day 1, etoposide 120 mg/m2 days 1-3 and bleomycin 60,000 U over 2 days (EBCa). Treatment was repeated every 3 weeks and a maximum of four courses was given. RESULTS: Of the 19 patients, 7 (37%) achieved complete remission, of whom 6 (32%) remained long-term progression-free. Post-chemotherapy surgery and further chemotherapy salvaged an additional 26%, leading to an overall disease-free survival rate of 58%. No relationship between outcome and degree of myelosuppression could be established. CONCLUSION: Dose-escalated carboplatin in combination, although feasible, did not improve the results and led to poorer results than those expected with cisplatin-based therapy. There is no evidence that the patients relapsing following this were easier to salvage. Further investigation of this regimen cannot be recommended.
Loss of CD30 expression in metastatic embryonal carcinoma: the effects of chemotherapy?
AIMS: CD30 has been shown to be consistently strongly expressed in embryonal carcinomas. Our aim was to examine changes in CD30 expression in embryonal carcinomas before and after treatment with chemotherapy. METHODS AND RESULTS: One hundred and eighteen retroperitoneal lymph node dissections from patients with metastatic germ cell tumours were reviewed. Seventeen contained embryonal carcinoma deposits. In nine cases, the matching pre-chemotherapy orchidectomy specimens were available. The cases were immunohistochemically stained for CD30. All nine pre- chemotherapy orchidectomy specimens showed embryonal carcinoma and stained strongly positively for CD30. However, only four out of nine of the matched post-chemotherapy retroperitoneal lymph node dissection specimens and a total of six out of 17 (35%) with embryonal carcinoma deposits stained for CD30. Ten seminomas were negative for CD30. Loss of CD30 did not appear to influence the relapse rate of the patients. CONCLUSIONS: Loss of CD30 expression occurs frequently in metastatic embryonal carcinomas after chemotherapy. This finding has implications in the use of CD30 in the diagnosis of metastatic non-seminomatous germ cell tumours and suggests that chemotherapy may alter the immunophenotype of embryonal carcinoma while retaining its characteristic histological appearances.
Testicular cancer.
A report of a 5-year survival rate of 39% for all patients with testis cancer in Kenya contrasts sharply with the 62% 5-year survival rate after tandem high-dose chemotherapy in first-line salvage of metastatic nonseminoma, and this figure provides a stark reminder of the differences in level of health care in the world. Nothing matches, however, the international significance of the success of Lance Armstrong in winning the Tour de France for the second time. It brings home the message of how complete the cure of this disease is and the need for more to be done to educate people about this success and encourage us to seek to discover the scientific basis for why this cancer is so different from all other cancers. The discovery that Lance Armstrong's brain metastases were totally necrotic at day 21 after the first treatment, taken with a report on the use of day 21 computed tomograph response to predict outcome, reinforces that message. With a second report suggesting that there are regions of the world that may have escaped the environmental damage to fertility that is now increasingly accepted as the most significant risk factor for development of this disease, we also need to remember the importance of germ cells as a weather vane of the environment. The first breakthrough in identifying a specific genetic region on the X chromosome with susceptibility to germ cell cancer of the testis by its association with development of undescended testis was one of the scientific landmarks of this past year. Clinically, with such high cure rates after salvage treatments, most of the controversy focuses now on early management of this disease. Debate continues regarding the need for orchidectomy or node dissection before chemotherapy in patients with metastases. There is also considerable debate concerning the need for any adjuvant treatment in stage 1 disease, whether surgical, chemotherapeutic, or radiotherapeutic. With reviews on late events highlighting the possibility that cisplatin dosage may be critical in synergizing with etoposide in causing leukemia and late cardiovascular events and reports suggesting that circulating cisplatin can be detected in the plasma as long as 20 years after treatment, the message of the year is clearly how to safely minimize the amount of treatment.
The characterisation of the lymphoma cell line U937, using comparative genomic hybridisation and multi-plex FISH.
The cell line U937, which has been used extensively for studies of myeloid differentiation, bears the t(10;11)(p13;q14) translocation which results in a fusion between the MLLT10 (myeloid/lymphoid or mixed-lineage leukemia [trithorax, Drosophila, homolog]; translocated to 10; alias AF10) gene and the Ap-3-like clathrin assembly protein, PICALM (Clathrin assembly lymphoid myeloid leukaemia). Apart from this translocation, very little is known about the other genetic alterations in this cell line that may represent significant events in disease progression. In this study, conventional G-banding, CGH and M-FISH have been used to characterise fully all of the cytogenetic alterations present in the U937 cell line. M-FISH analysis confirmed the presence of the t(10;11) and an apparently normal copy of both chromosomes 10 and 11. A t(1;5) translocation was observed as well as several unbalanced rearrangements. CGH detected amplifications resulting from duplications of 2q, 6p and 13q. These changes could result in fusion gene products involved in carcinogenesis or the positions of putative oncogenes and tumour suppressor genes. A good correlation between conventional G-banding, CGH and M-FISH was observed.
Testicular microlithiasis: is it a benign condition with malignant potential?
OBJECTIVE: To review the findings of testicular ultrasonography (US) in patients referred for testicular symptoms including pain, swelling and infertility, and to determine the prevalence of testicular microlithiasis (TM) and ist relevance to the development of testicular cancer. METHODS: Records of 3,026 patients referred for testicular US between 1994 and 1999 were evaluated. The indications for testicular US diagnosis, management and relevant histological details were obtained from medical records. Patients with TM had an annual sonographic follow-up unless they had testicular cancer, in which case follow-up repeat US with clinical reviews was more frequent. RESULTS: TM was found in 54 patients (1.77%; median age 34 years, range 12-83 years). The median follow-up was 36 months (range 12-18 months). Sixteen of these patients had testicular malignancy (30%). The remaining 38 patients had hydrocele and epididymal cysts (14), varicocele (7), epididymitis (2) and small testes (8), with 14 patients having no other pathology. One patient with a small testis developed a seminoma while under surveillance. Another patient with metastatic embryonal-cell carcinoma at initial diagnosis was found to have a seminoma 4 years following chemotherapy. The relative risk of testicular tumours in the presence of TM was 13.2 (confidence interval 8.3-21.5). CONCLUSION: TM can no longer be regarded simply as a benign condition because of its association with testicular malignancy. In our series, 2 patients (5.2%) developed interval testicular cancers during follow-up US. There is no convincing evidence to suggest that TM might be premalignant. In rare instances of radiologically indeterminate cases, biopsy of the testis may be necessary.
Phase 1/2 study of synchronous methotrexate, cisplatin, vincristine (MOPq10) chemotherapy and radiation for patients with locally advanced bladder cancer.
PURPOSE: This phase 1/2 study was designed to test toxicity and effectiveness of combination chemotherapy and concurrent radiotherapy in the treatment of invasive bladder cancer. METHODS AND MATERIALS: 17 patients with localised muscle-invasive bladder cancer, clinical stages T2-3 N0, M0, were treated with a radiotherapy schedule of 55 Gy in 20 fractions over 4 weeks restricted to the bladder and 3 cycles of concurrent dose-intensive combination chemotherapy consisting of cisplatin 60 mg/m(2), vincristine 2 mg and methotrexate 60 mg/m(2) at 10-day intervals (MOPq10). RESULTS: The complete remission rate following MOPq10 chemotherapy and radiotherapy was 88% as assessed at first cystoscopy with 82% remaining disease-free at 1 year. Risk factor analysis shows those older than 63 years (median) and those with creatinine clearance equal or less than the mean did worse. Actuarial disease-free survival at 2 years was 68% and of the patients treated 4/17 experienced acute G3/4 toxicity. CONCLUSION: This combination regimen was feasible. Its high initial response rate justifies further exploration in a randomised phase 2/3 trial setting with bladder volume and quality of life assessment.
Male circumcision and HIV prevention. More studies need to be done before widespread circumcision is implemented.
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Management of women with early breast cancer. New strategies are needed to address inequalities.
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Though HIV is the main cause of AIDS, other factors play a role.
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The combined use of high performance liquid chromatography and immuno-biochemical techniques for protein isolation: a new approach for identification of an individual protein from a pool of proteins.
HPLC was used in combination with immuno-bead separation technique for identification of an individual protein from a pool of proteins. This was carried out using an in-house monoclonal antibody (ATC2) specific for placental alkaline phosphatase (PLAP) as a primary antibody for conjugation to CNBr beads. The phosphatase activity (ALP) of PLAP was measured by colorimetric assay (MEDC). The data from this study has so far indicated that: 1. HPLC analysis of molecules following isolation with ATC2-conjugated beads showed high degree of purity. This could be achieved using protein mixtures prepared from lysates of tumour cell lines or tumour fragments. 2. HPLC-isolated PLAP maintained phosphatase activity. 3. Out of the four dissociation reagents used, diethyl amine (DEA) was found to be the best reagent for dissociation of antigen, ie PLAP, but not mAb from CNBr beads. 4. The profile of ALP activity was different for samples prepared from testis and kidney fragments, both in terms of the HPLC peak profile as well as the sensitivity. These data confirmed that the immuno-bead separation technique in conjunction with HPLC were powerful tools for identifying an individual protein from a pool of proteins. These approaches are being used for the identification of PLAP molecules, as a tumour marker in patients suspected of testicular malignancies with equivocal ultrasound.
Stilboestrol plus adrenal suppression as salvage treatment for patients failing treatment with luteinizing hormone-releasing hormone analogues and orchidectomy.
OBJECTIVE: To investigate the efficacy of low-dose stilboestrol (SB) with hydrocortisone in patients with advanced prostate cancer refractory to androgen suppression. PATIENTS AND METHODS: Thirty-four consecutive patients (median age 70 years, range 51-83) with metastatic disease who progressed on hormone therapy, as shown by recurrent/worsening symptoms and an increase in prostate-specific antigen (PSA) level, were recruited and discontinued hormonal treatment before starting SB. Patients received SB (1 mg/day) combined with hydrocortisone (40 mg/day). In an attempt to reduce the incidence of thrombo-embolic events, aspirin (75 mg/day) was also added. RESULTS: Stilboestrol was the second-line treatment in 19 patients and the third or fourth in 15. The median (range) duration of treatment with SB was 5 (0.5-21) months and the median follow-up 7.5 months, with 18 patients still alive and 14 still on treatment. Of 29 symptomatic patients, 24 had symptomatic improvement and five had no clear benefit; the median duration of benefit was 6 (2-21) months. The PSA level decreased by 0-50% in six patients, by 50-90% in 13 and by > 90% in eight, while there was symptomatic improvement in these three categories in five, 11 and seven patients, respectively. The median times to PSA nadir and progression were 4 and 6 months, respectively. Some thrombo-embolic events and fluid retention occurred but overall the treatment was well tolerated. CONCLUSION: Low-dose SB with hydrocortisone is effective in refractory prostate cancer, although there is some toxicity. Randomized studies against hydrocortisone or SB alone are needed to establish the cost/benefit ratio of this combination.
Computed tomography 21 days after chemotherapy, three-dimensional estimates of metastatic volume and the need for surgery in patients with germ cell cancer.
OBJECTIVE: To assess whether the response visible on computed tomography (CT) 21 days after the first course of chemotherapy in patients with nonseminomatous germ cell tumour predicts the need for surgery and whether three-dimensional (3D) reconstruction adds to the diagnostic accuracy. PATIENTS AND METHODS: CT scans from 52 patients treated with cisplatin-based chemotherapy were assessed for tumour shrinkage by measuring the changes of a one-dimensional (1D) measurement of the maximum transverse diameter, and comparing CT scans before, 21 days after the first course and at the end of chemotherapy (1D method). In a subset of patients, using a special formula, the 1D-derived 2D and 3D shrinkage (2Dder and 3Dder) were compared with four other computed or calculated methods (1D, 2D, 3Dcalc, 3Dcomp). RESULTS: At day 21, in 32 of 52 patients (62%) there was < 50% tumour shrinkage using the 1D assessment; 21 of them (66%) needed surgery, compared with none of the 20 patients with > 50% tumour shrinkage by day 21 (chi2 = 22.83, P < 0.001). The 1D method showed significantly less shrinkage than all the other methods but when this was used to derive a 3D shrinkage, assuming the mass to be spherical (3Dder), it was not statistically different from that of 3Dcomp. CONCLUSIONS: The assessment of the response from 1D CT scan estimates 21 days after initiating chemotherapy identifies a subgroup of patients who have a high probability of needing surgery. Although expected to be more accurate, the 3Dcomp estimate of tumour shrinkage was no better than the 3Dder estimate.
Pre-induction LDH as a prognostic factor for outcome of high dose chemotherapy (HDCT) for germ cell tumours relapsing or refractory to conventional chemotherapy.
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Evidence for a schedule-dependent deleterious interaction between paclitaxel, vinblastine and cisplatin (PVC) in the treatment of advanced transitional cell carcinoma.
A phase II study to evaluate the efficacy and toxicity of the combination of vinblastine, paclitaxel and cisplatin (PVC) in previously untreated patients with advanced transitional cell carcinoma. Chemotherapy naive patients with locally advanced or metastatic transitional cell carcinoma received the intravenous combination of paclitaxel 175 mg/m(2)over three hours followed by cisplatin 70 mg/m(2)over 3 hours on day 1 and vinblastine 3 mg/m(2)as a bolus on days 1 and 8 on a 21-day cycle, to a maximum of 6 cycles. The day 8 vinblastine was omitted if the total neutrophil count was <1.0. 15 patients (13 M, 2 F) of median age 66 (54-75) received a median of 5 cycles of treatment. There were two complete responses (13%; 95% CI 2-40%) and five partial responses (33%; 95% CI 12-62%), for an overall response rate of 46% (95% CI 21-73%). Responses occurred only in those with locally recurrent tumours and/or lymph nodes involved. Neutropenia at Grade 3-4 occurred in 14 of 67 cycles (21%) resulting in 7 episodes of neutropenic sepsis. Grade 3-4 thrombocytopenia was not observed. Other Grade 3 toxicity included alopecia (10 pts), diarrhoea (2 pts), constipation resulting in bowel obstruction (2 pts), nephrotoxicity (1 pt), myalgic pain (1 pt) and peripheral neuropathy (1 pt). Six patients developed Grade 2 paraesthesia. The median time to progression was 6 months and the median survival was 11 months. The regimen PVC was both less effective against transitional cell carcinoma and less toxic than expected. This may reflect an inhibitory interaction between vinblastine and paclitaxel and this schedule cannot be recommended for further investigation.