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Biomedical subjects

J Sturgeon

Publications and source records attributed to J Sturgeon.

At least 19 recordsLinked to original sources

Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus.

The aims of this study were reviewing our experience regarding the pulmonary toxicity of the mammalian target of rapamycin (mTOR) inhibitor temsirolimus, discussing potential pathogenic mechanisms and proposing management strategies. Medical records and radiological reports of 22 patients treated with weekly doses of temsirolimus 25 mg were reviewed. Eight (36%) out of 22 patients developed pulmonary abnormalities compatible with drug-induced pneumonitis. Half were asymptomatic and in those with symptoms, dyspnea and dry cough were the most common. Radiologically two different patterns, ground glass opacities and lung parenchymal consolidation, were described. The management of this toxicity was variable, ranging from no intervention to discontinuation of the drug. In our experience temsirolimus may cause drug-induced pneumonitis at a higher incidence than that previously reported. The presentation and its severity are variable. The risk of developing this toxicity may be increased among subjects with abnormal pre-treatment pulmonary functions or history of lung disease.

Adult↗

Strengths and limitations of molecular subtyping in a community outbreak of Legionnaires' disease.

An epidemiological and microbiological investigation of a cluster of eight cases of Legionnaires' disease in Los Angeles County in November 1997 yielded conflicting results. The epidemiological part of the investigation implicated one of several mobile cooling towers used by a film studio in the centre of the outbreak area. However, water sampled from these cooling towers contained L. pneumophila serogroup 1 of another subtype than the strain that was recovered from case-patients in the outbreak. Samples from two cooling towers located downwind from all of the case-patients contained a Legionella strain that was indistinguishable from the outbreak strain by four subtyping techniques (AP-PCR, PFGE, MAb, and MLEE). It is unlikely that these cooling towers were the source of infection for all the case-patients, and they were not associated with risk of disease in the case-control study. The outbreak strain also was not distinguishable, by three subtyping techniques (AP-PCR, PFGE, and MAb), from a L. pneumophila strain that had caused an outbreak in Providence, RI, in 1993. Laboratory cross-contamination was unlikely because the initial subtyping was done in different laboratories. In this investigation, microbiology was helpful for distinguishing the outbreak cluster from unrelated cases of Legionnaires' disease occurring elsewhere. However, multiple subtyping techniques failed to distinguish environmental sources that were probably not associated with the outbreak. Persons investigating Legionnaires' disease outbreaks should be aware that microbiological subtyping does not always identify a source with absolute certainty.

Adult↗

Treatment of early epithelial ovarian cancer with chemotherapy and abdominopelvic radiotherapy: results of a prospective treatment protocol.

PURPOSE: To test the hypothesis that the combination of adjuvant chemotherapy and abdominopelvic radiation (APRT) improves the outcome of patients with early ovarian cancer compared to treatment with APRT alone. METHODS AND MATERIALS: Between 1991 and 1994, 93 patients with Stage I to III, optimally cytoreduced, invasive, epithelial ovarian cancer were treated with sequential chemotherapy and APRT. Treatment was assigned using a prognostic classification that was derived from previous cohorts of patients. Low-risk patients (n = 9) received APRT alone, intermediate-risk patients (n = 66) received two courses of cisplatin followed by APRT, and high-risk patients (n = 18) received 6 courses of cisplatin and cyclophosphamide followed by APRT. RESULTS: Disease recurred in 22 patients, and was confined to the pelvis or abdomen in 15. Nine patients died and the remainder were alive with disease after receiving salvage chemotherapy. The 3-year disease-free and overall survivals were 78% and 91%, respectively. The prognostic classification used to assign treatment was the only factor that predicted disease-free survival (83% and 59% at 3 years for low/intermediate- and high-risk patients, respectively; p = 0.03). There was no detectable difference in outcome between the present series and an historical control group treated with APRT alone. Treatment was well tolerated and only 2 patients (2.5%) developed serious complications. CONCLUSION: APRT is an effective adjuvant treatment for carefully selected patients with early ovarian cancer. The addition of chemotherapy as used in this study to APRT does not significantly improve outcome compared to APRT alone.

Adult↗

Risk of leukemia after platinum-based chemotherapy for ovarian cancer.

BACKGROUND: Platinum-based chemotherapy is the cornerstone of modern treatment for ovarian, testicular, and other cancers, but few investigations have quantified the late sequelae of such treatment. METHODS: We conducted a case-control study of secondary leukemia in a population-based cohort of 28,971 women in North America and Europe who had received a diagnosis of invasive ovarian cancer between 1980 and 1993. Leukemia developed after the administration of platinum-based therapy in 96 women. These women were matched to 272 control patients. The type, cumulative dose, and duration of chemotherapy and the dose of radiation delivered to active bone marrow were compared in the two groups. RESULTS: Among the women who received platinum-based combination chemotherapy for ovarian cancer, the relative risk of leukemia was 4.0 (95 percent confidence interval, 1.4 to 11.4). The relative risks for treatment with carboplatin and for treatment with cisplatin were 6.5 (95 percent confidence interval, 1.2 to 36.6) and 3.3 (95 percent confidence interval, 1.1 to 9.4), respectively. We found evidence of a dose-response relation, with relative risks reaching 7.6 at doses of 1000 mg or more of platinum (P for trend <0.001). Radiotherapy without chemotherapy (median dose, 18.4 Gy) did not increase the risk of leukemia. CONCLUSIONS: Platinum-based treatment of ovarian cancer increases the risk of secondary leukemia. Nevertheless, the substantial benefit that platinum-based treatment offers patients with advanced disease outweighs the relatively small excess risk of leukemia.

Aged↗

Effect of filgrastim (G-CSF) during chemotherapy and abdomino-pelvic radiation therapy in patients with ovarian carcinoma.

PURPOSE: To evaluate the safety and effectiveness of filgrastim (granulocyte colony-stimulating factor, G-CSF) in reducing neutropenia and treatment interruptions during whole abdominal radiotherapy for ovarian cancer. METHODS AND MATERIALS: Sixteen patients with ovarian cancer treated with 2 to 6 courses of cisplatin-containing chemotherapy and abdomino-pelvic radiation therapy received filgrastim for neutrophil counts <2 x 10(9)/L. Endpoints for analysis included the ability to maintain the neutrophil count in the target range, number of treatment interruptions due to neutropenia, and toxicity attributed to filgrastim. RESULTS: Fourteen patients received a mean of 2.9 courses of filgrastim (each with a mean duration of 4.1 days), with no treatment interruptions due to neutropenia. The majority of neutrophil counts were maintained above the target range of 2 x 10(9)/L during treatment. Thrombocytopenia requiring treatment interruption was seen in six patients and necessitated platelet transfusions in one. Thrombocytopenia occurred at a mean abdominal radiation dose of 2207 cGy and in all but one patient was preceded by one or more episodes of neutropenia. In comparison with a control group of 31 patients treated without filgrastim there was no reduction in treatment interruptions. Four patients did not complete treatment because of persistent thrombocytopenia yet received a mean of 94% of the planned abdominal radiation dose and 69% of the planned pelvic dose. Filgrastim toxicity was limited to mild skeletal pains in six patients and a Grade 1 skin rash in two patients. CONCLUSIONS: Filgrastim is safe and effective in preventing neutropenia and reducing neutropenic treatment interruptions during abdominal radiotherapy in patients with ovarian cancer. However, there was no clear benefit to the use of filgrastim as thrombocytopenia became the dose-limiting toxicity resulting in a risk of treatment interruptions and early termination of radiotherapy.

Abdomen↗

Management of stage II seminoma.

PURPOSE: To assess the results of treatment, patterns of failure, and prognostic factors for relapse in a contemporary cohort of patients with stage II seminoma. MATERIALS AND METHODS: From January 1981 and December 1993, 99 patients (median age, 35 years) with stage II seminoma (IIA, 41; IIB, 28; IIC, 24; IID, six) were managed at our institution. Eighty were treated with radiation therapy (RT) and 19 with chemotherapy (ChT). RESULTS: With a median follow-up of 6.7 years, the five-year overall actuarial survival was 94%, the 5-year cause-specific survival was 94%, and the 5-year relapse-free rate was 83%. Sixteen (20%) of the 80 patients treated with RT relapsed (median time to relapse, 9 months). Relapse occurred outside the irradiated area in all but two patients. Distant relapse sites included the supraclavicular fossa, bone (four patients, three with spinal cord compression), and lung/mediastinum. All 19 patients treated primarily with ChT achieved disease control and none has relapsed. The relapse rate at 5 years for patients with stage IIA to IIB was 11% (seven of 64), and 56% (nine of 16) for those with stage IIC to IID disease (P < .0001). No patient with IIC or IID disease treated with ChT relapsed as compared with 56% of patients treated with RT (0 of 14 v nine of 16, P = .002). CONCLUSION: Radiation therapy is highly effective in patients with stage IIA or IIB seminoma (89% were relapse free). In stage IIC or IID disease, although local control with RT is excellent, a 50% risk of distant relapse is unacceptable, and not all patients who relapse can be salvaged. Chemotherapy should clearly be the primary treatment in patients with stage IIC or IID seminoma.

Adult↗

Risk of second malignant neoplasms among long-term survivors of testicular cancer.

BACKGROUND: We have quantified the site-specific risk of second malignant neoplasms among nearly 29,000 survivors (> or = 1 year) of testicular cancer, taking into account the histologic type of initial cancer and the primary therapy used to treat it. METHODS: The study cohort consisted of 28,843 men identified within 16 population-based tumor registries in North America and Europe; over 3300 men had survived more than 20 years. New invasive cancers were identified through a search of registry files. RESULTS: Second cancers were reported in 1406 men (observed-to-expected ratio [O/E] = 1.43; 95% confidence interval = 1.36-1.51), with statistically significant excesses noted for acute lymphoblastic leukemia (O/E = 5.20), acute nonlymphocytic leukemia (O/E = 3.07), melanoma (O/E = 1.69), non-Hodgkin's lymphoma (O/E = 1.88), and cancers of the stomach (O/E = 1.95), colon (O/E = 1.27), rectum (O/E = 1.41), pancreas (O/E = 2.21), prostate (O/E = 1.26), kidney (O/E = 1.50), bladder (O/E = 2.02), thyroid (O/E = 2.92), and connective tissue (O/E = 3.16). Overall risk was similar after seminomas (O/E = 1.42) or nonseminomatous tumors (O/E = 1.50). Risk of solid tumors increased with time since the diagnosis of testicular cancer, yielding an O/E = 1.54 (O = 369) among 20-year survivors (two-sided P for trend = .00002). Secondary leukemia was associated with both radiotherapy and chemotherapy, whereas excess cancers of the stomach, bladder, and, possibly, pancreas were associated mainly with radiotherapy. CONCLUSIONS: Men with testicular cancer continue to be at significantly elevated risk of second malignant neoplasms for more than two decades following initial diagnosis. Patterns of excess second cancers suggest that many factors may be involved, although the precise roles of treatment, natural history, diagnostic surveillance, and other influences are yet to be clarified.

Antineoplastic Agents↗

Cost-utility analysis of paclitaxel in combination with cisplatin for patients with advanced ovarian cancer.

The standard treatment for patients with advanced ovarian cancer (AOC) has been cyclophosphamide and cisplatin (CP). Recently, the results of a large randomized comparative trial demonstrated that the combination of paclitaxel and cisplatin (TP) provided a progression-free survival benefit of 5 months. In this study, a cost-utility analysis was performed from a Canadian health care system perspective to estimate the incremental cost-effectiveness of the TP combination. Twelve AOC patients who received treatment with TP were matched for age and disease stage on a 1-to-2 basis with a CP control. Total hospital resource consumption was then collected for all patients. Treatment preferences were estimated from a cohort of 20 patients and 40 healthy female volunteers using the time trade-off technique. The outcomes were then generated through a decision-analytic model. First-line treatment costs with TP were approximately fourfold greater on a per-cycle basis than the CP alternative (Can$1911 vs Can$459). When progression-free survival benefit and patient treatment preferences were incorporated into the analysis, the results of the decision model revealed an incremental cost between Can$12,000 and Can$24,000 per quality-adjusted progression-free year with the TP protocol. Even though the TP combination has a considerably higher drug acquisition cost, the results of the current analysis suggest that this new chemotherapy regimen does provide patients with substantial quality-adjusted progression-free survival benefit at a reasonable cost to the Canadian health care system.

Adult↗

Resource implications of palliative chemotherapy for ovarian cancer.

PURPOSE: To describe the costs and outcomes of palliative chemotherapy in women with recurrent and refractory ovarian cancer from the perspective of a health care provider. PATIENTS AND METHODS: A retrospective study of 40 consecutive women who started second- or third-line chemotherapy for recurrent or refractory ovarian cancer between 1989 and 1992. Resource utilization from the commencement of second- or third-line chemotherapy until death or last follow-up evaluation was determined from a detailed chart review. All elements of care were recorded, including inpatient admissions, outpatient visits, chemotherapy drugs, nonchemotherapy drugs, radiation therapy, surgical procedures, investigations, and home care. Costs calculated using the hotel-approximation method are expressed in 1994 Canadian dollars. Actuarial estimates of cost and survival were used to account for censored observations. RESULTS: After a minimum follow-up period of 24 months, 36 of 40 women had died. The median survival duration of the group was 1.1 years from study entry and 1.7 years from first relapse. The women received a median of two regimens of chemotherapy (range, one to four) from study entry. They spent a median of 33 days as hospital inpatients (mean, 46; range, 0 to 185); 58% of these inpatient days were for symptomatic management and 32% were for chemotherapy. The mean cost per patient was $53,000 (median, $36,600; range, $4,800 to $162,900). The relationship between cost and survival duration was not linear--the cost per year was lowest for those who lived longest. Inpatient admissions, chemotherapy drugs, and outpatient visits accounted for 62%, 21%, and 8% of the total cost, respectively. The total costs attributable to chemotherapy were $24,000 (45% of total costs) and the total costs attributable to supportive care were $23,000 (43% of total costs). CONCLUSION: These data illustrate the cost of palliative management of recurrent and refractory ovarian cancer, which must be considered in the context of quality and duration of survival. They indicate the potential to improve cost efficiency by improving resource management, for example, by shifting from inpatient to outpatient chemotherapy, everything else being equal.

Adult↗

Benefit of palliative surgery for bowel obstruction in advanced ovarian cancer.

OBJECTIVES: To determine the benefit of palliative surgery for patients with advanced ovarian cancer and bowel obstruction and to identify criteria for selecting patients who are most likely to benefit from palliation. DESIGN: A retrospective study of patients treated between 1982 and 1992. SETTING: A university-affiliated hospital. PATIENTS: Fifty-three patients with complete and unresolved bowel obstruction caused by ovarian cancer. INTERVENTION: Surgery for relief of bowel obstruction. MAIN OUTCOME MEASURES: Postoperative survival longer than 60 days, return home and relief of bowel obstruction for longer than 60 days, factors associated with failure of palliative surgery. RESULTS: Successful palliation was achieved in 27 (51%) patients and was associated with the absence of four prognostic factors: palpable abdominal and pelvic masses, ascites exceeding 3 L, multiple obstructive sites and preoperative weight loss greater than 9 kg. Age, time interval between diagnosis of ovarian cancer and bowel obstruction, stage of disease at initial diagnosis, tumour type and grade, site and degree of obstruction, presence of gross residual tumour after initial operation and preoperative use of chemotherapy or radiotherapy did not indicate the success or failure of palliative surgery. CONCLUSIONS: Palliative surgery for bowel obstruction in advanced ovarian cancer can be worthwhile, and there are four prognostic factors that indicate the likely failure of palliation.

Aged↗

High-dose methotrexate for gestational trophoblastic disease.

Eighty patients with low-risk and 5 patients with intermediate-risk gestational trophoblastic neoplasia (GTN) (WHO classification) were treated with single-agent high-dose methotrexate with folinic acid rescue (MTX/FAR). By the NCI classification, 65 patients had nonmetastatic GTN, 13 patients had low-risk metastatic GTN, and 7 patients had high-risk metastatic GTN. Seventy-one (84%) patients achieved remission (beta HCG < or = 5 IU/liter) with MTX/FAR, whereas 14 (16%) failed to achieve remission with MTX/FAR alone. All failures were salvaged with second-line therapies. Patients successfully treated with MTX/FAR required a median of 4 courses to achieve remission, and a median of 2 consolidative courses. Factors found predictive of failure with MTX/FAR were pretreatment beta HCG (P = 0.003), prior history of GTN (P < 0.04), and time from termination of antecedent pregnancy to initiation of treatment (P < 0.05). No significant difference was noted between the "success" and "failure" groups with respect to MTX dose or infusion time, the timing and dosage of folinic acid rescue, the number of courses of MTX, or the mean interval between courses. Multivariate analysis revealed that the pretreatment beta HCG (P < 0.01) and short time from termination of antecedent pregnancy to initiation of treatment (P < 0.03) were independently significant for failure. No significant (grade 3/4) hematologic or gastrointestinal toxicity occurred, and no treatment delays or dose reductions were required. This regimen is both effective and well tolerated; however, the theoretical advantages of high-dose methotrexate do not appear to offer any clinical advantage over conventional dose MTX in low- and intermediate-risk GTN.

Biomarkers, Tumor↗

Bleomycin-induced pulmonary function abnormalities.

The usefulness of serial PFTs in identifying patients who are developing BIP was assessed in 59 men with non-seminomatous testicular carcinoma. The mean age was 27.7 years and all the patients received a standard three-course chemotherapy regimen consisting of vinblastine, bleomycin, and cis-diamminedichloroplatinum. The average dose of bleomycin was 555.5 units. Serial PFTs, chest roentgenograms, and medical assessments were done prior to each course of bleomycin. Nine (15.3 percent) patients developed pulmonary symptoms due to bleomycin and 23 (39 percent) had significant changes on chest x-ray films. The Dsb dropped significantly with bleomycin treatment; therefore, it is the most sensitive indicator of pulmonary response to bleomycin. However, the Dsb failed to differentiate patients with BIP from those without. The TLC was found to be a much more specific indicator of BIP because reduction in TLC correlated with the development of pulmonary symptoms and roentgenologic changes.

Adolescent↗

An assessment of combined tumour markers in patients with seminoma: placental alkaline phosphatase (PLAP), lactate dehydrogenase (LD) and beta human chorionic gonadotrophin (beta HCG).

We have assessed the tumour markers placental alkaline phosphatase (PLAP), lactate dehydrogenase (LD), and human chorionic gonadotrophin (beta HCG) using 2,000 serum samples from 286 patients with seminoma. The ROC curves show that no one marker performs adequately for the detection of disease either at initial staging or during follow-up. We used a Markov model heuristically to devise strategies, in which marker results were assessed in combination, which might be useful in clinical practice. We found that the best strategy was to consider a test result abnormal only if either the beta HCG was greater than 6 Ul-1 or the LD was greater than 400 U l-1 and the PLAP level was greater than 60 U l-1. This will detect about 50% of patients with disease and the false-positive rate is 2%. In practical terms this means that PLAP need only be estimated in patients whose beta HCG is less than 6 IU l-1 and whose LD is greater than 400 U l-1.

Alkaline Phosphatase↗

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.

Adult↗

Concurrent radiation, mitomycin C and 5-fluorouracil in poor prognosis carcinoma of cervix: preliminary results of a phase I-II study.

Between July 1981 and June 1983, 27 patients with advanced primary squamous cell carcinoma (SCC) of cervix (FIGO Stages IIIB, IVA or extensive nodal involvement) and 8 with recurrent disease were treated using a pilot regimen of combination chemotherapy (CT): Mitomycin C (MIT), 5 Fluorouracil (5 FU), and radiation therapy (RT). CT and RT doses on this Phase I-II Study were escalated to the current regimen. A split course of RT was used, either pelvic RT alone (4560 Gy in 28 fractions) or the same pelvic RT plus para-aortic RT (3600 Gy in 24 fractions). CT was given: MIT 6 mg/M2 IV push day 1, and 5 FU 1.0 g/M2 (maximum daily 1.5 g) by continuous IV infusion days 1 through 4 of each half-course of RT. This was followed by one application of intrauterine 137Cs when possible. Three of the 8 patients with recurrence in the pelvis or para-aortic nodes had a complete response (CR) to CT-RT and are alive without disease at 19, 19 and 22 months after treatment, respectively. Twenty of the 27 (74%) primary patients had a CR. With a median duration of follow-up of 6 months 4/20 have relapsed, 1 in RT field, 2 at distant sites, and 1 in both. Pelvic disease remains controlled in 19/27 (70%) including one patient salvaged with surgery. The acute toxicity of this regimen was tolerable: 2/35 developed transient leukopenia with one febrile episode, 9/35 developed transient thrombocytopenia without bleeding. Symptomatic sigmoid strictures developed in two patients, one requiring surgical intervention. Sigmoid perforation occurred in one patient and contributed to death. Typically, near complete regression of tumor is noted on completion of the external RT, reproducing the dramatic responses that have been observed in SCC of the anal canal, esophagus and head and neck, with this CT-RT regimen. A Phase III Study is required to establish whether the enhanced response rates to CT-RT will result in increased pelvic control and cure rates compared to those after RT alone.

Antibiotics, Antineoplastic↗

Ovarian carcinoma: improved survival following abdominopelvic irradiation in patients with a completed pelvic operation.

A prospective, stratified, randomized study of 190 postoperative ovarian patients with Stages IB, II, and III (asymptomatic) presentations is reported. The median time of follow-up was 52 months. Patients in whom bilateral salpingo-oophorectomy and hysterectomy (BSOH) could not be completed because of extensive pelvic tumor had a poor prognosis which did not differ for any of the therapied tested. When BSOH was completed, pelvic plus abdominopelvic irradiation (P + AB) with no diaphragmatic shielding significnatly improved patient survival rate and long-term control of occult upper abdominal disease in approximately 25% more patients than pelvic irradiation alone or followed by adjuvant daily chlorambucil therapy. The effectiveness of P + AB in BSOH-completed patients was independent of stage or tumor grade and was most clearly appreciated in patients with all gross tumor removed. Chlorambucil added to pelvic irradiation delayed the time to treatment failure without reducing the number of treatment failures.

Abdomen↗

Treatment of epithelial carcinoma of the ovary: operation, irradiation, and chemotherapy.

This paper presents an interim analysis of 279 patients with epithelial carcinoma of the ovary who were entered into a prospective study started in April, 1971. One hundred and three patients were available for analysis three years after diagnosis. Apart from the survival differences by stage and treatment method, this study has shown that the completeness of the initial pelvic operation, in Stages II and III, is of greater prognostic importance than the stage. The importance of the features of the pelvic disease which interfere with the removal of all pelvic organs led the authors to conclude that factors other than stage should be considered in prescribing postoperative treatment. To date, the disease-free survival trends in Stages IB, II, and asymptomatic Stage III show that physicians should place much greater emphasis on the initial operative features when they are seeking the most effective combination of irradiation and chemotherapy. Analysis of failures shows that upper abdominal irradiation is more effective than daily chlorambucil in preventing progression of disease to that area. However, early evidence indicates that chlorambucil added to pelvic irradiation improves the control of pelvic disease. Improved methods of treatment have not yet been identified for early Stage I (IA) and advanced presentations (symptomatic Stages III and IV).

Abdomen↗