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J Glaholm

Publications and source records attributed to J Glaholm.

33 records · Page 2Linked to original sources
PubMed1993

The non-invasive monitoring of low dose, infusional 5-fluorouracil and its modulation by interferon-alpha using in vivo 19F magnetic resonance spectroscopy in patients with colorectal cancer: a pilot study.

BACKGROUND: 5-Fluorouracil (5-FU) is the most widely used cytotoxic drug in oncology and the only one useful in the management of colorectal cancer - a leading cause of cancer death worldwide. Recent studies of 5-FU have focused on increasing efficacy and reducing toxicity by varying the delivery schedule and combining it with modulators. With the development of whole body magnetic resonance systems it is now possible to examine the metabolism of 5-FU in vivo by exploiting the magnetic properties of the fluorine atom which is an integral component of the drug. PATIENTS AND METHODS: Magnetic Resonance Spectroscopy (MRS) was used to non-invasively monitor the metabolism of 5-FU in the liver metastases of colorectal cancer patients. The patients were treated with a continuous low dose intravenous infusion of 5-FU until the point of refractory disease, at which time interferon-alpha was added with the objective of modulating 5-FU activity. MRS was performed at specific phases of the treatment. RESULTS: Twenty-six patients were treated with 5-FU, 11 (42%) achieving partial response. Of the 15 given interferon when disease became refractory to 5-FU, 4 showed signs of further response. In patients observed by MRS during the first 8 weeks of 5-FU treatment, those with a visible 5-FU signal were likely to respond to treatment (p = 0.017). At the time of interferon-alpha addition, MRS showed that 7 patients developed new or increased 5-FU signals, and 4 patients showed a signal from the active metabolites of 5-FU. The patients who exhibited a new or increased 5-FU signal were more likely to show further response to interferon-alpha (p = 0.007). CONCLUSIONS: MRS is a powerful technique for monitoring intratumoural metabolism and modulation of 5-FU enabling prediction of tumour outcome. Direct metabolic information may facilitate the rapid development of optimal clinical schedules for 5-FU and its modulators, thus maximising antitumour effect and minimising toxicity to the patient. This technique may be applied to other areas of clinical medicine where knowledge of the tissue metabolism of a fluorinated drug is of interest.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Anatomically derived attenuation coefficients for use in quantitative single photon emission tomography studies of the thorax.

Elimination of errors due to poor attenuation correction is an essential part of any quantitative single photon emission tomography (SPET) technique. Attenuation coefficients (mu Tc) for use in attenuation correction of SPET data were determined using technetium 99m and cobalt 57 flood sources and using topographical information obtained from computed tomography (CT) scans and magnetic resonance (MR) images. In patients with carcinoma of the bronchus, the mean attenuation coefficient for 99mTc was 0.096 cm-1 when determined across a transverse section of the thorax at the level of the tumour by means of a 57Co flood source (13 patients) and 0.093 and 0.074 cm-1 as determined from CT scans for points in the centre of the tumour and contralateral normal lung, respectively (21 patients). In 18 patients with breast tumours, the mean attenuation coefficient for 99mTc was 0.110 and 0.076 cm-1 when determined from MRI cross-sections for points in the centre of the tumour and normal contralateral lung, respectively. This indicates significant overcorrection for attenuation when the conventional value of 0.12 cm-1 is used. A value in the range 0.08-0.09 cm-1 would be more appropriate for SPET studies of the thorax. An alternative approach to quantitative region of interest (ROI) analysis is to perform attenuation correction appropriate to the centre of each ROI (using topographical information derived from CT or MRI) on non-attenuation-corrected reconstructions.

Breast Neoplasms↗
PubMed1991

The effect of intra-tumour heterogeneity on the distribution of phosphorus-containing metabolites within human breast tumours: an in vitro study using 31P NMR spectroscopy.

The concentration of phosphorus-containing metabolites was determined in extracts of multiple samples from six human breast tumours and in samples from normal and inflamed breast tissue. The degree of lymphoid infiltrate, necrotic fraction and tumour cell and normal tissue fraction were determined on sections taken from each of the tumour samples. In four of the tumours there was a very high degree of variation between samples in the absolute concentration of metabolites. Three of these tumours showed a high degree of intra-tumour variation in the distribution of tumour cells and of normal tissue. The other two tumours were relatively homogeneous with respect to both tumour cellularity and the distribution of phosphorus-containing metabolites. Samples from normal breast tissue was found to contain only low concentrations of phosphorus-containing metabolites. However one of the inflamed samples, which consisted predominantly of macrophages, contained high levels of such compounds. The effect of time delay between resection and freezing on the levels of metabolites in human breast tumours was also examined.

Breast↗
PubMed1991

A comparison of in vivo and in vitro 31P NMR spectra from human breast tumours: variations in phospholipid metabolism.

An in vivo 31P NMR spectrum was obtained from each of four human breast tumours. The phosphomonoester and phosphodiester region of each spectrum consisted of a broad peak. Chemical extracts from samples of each of the tumours obtained at resection were examined on a high field strength NMR system. The phosphomonoester region in the spectrum from each extract resolved into three peaks consisting of phosphocholine, phosphoethanolamine and a nucleoside monophosphate. The phosphodiester region resolved into two components, glycerophosphorylcholine and glycerophosphorylethanolamine. Comparing the in vivo and in vitro data from each tumour showed that the contribution of phosphodiester was much lower in the in vitro spectra. We believe this to be a consequence of phospholipid, which would not appear in the aqueous extract, contributing to the phosphodiester peak in vivo.

Breast Neoplasms↗
PubMed1991

A phase II clinical and pharmacokinetic study of Lonidamine in patients with advanced breast cancer.

Lonidamine is a substituted indazole carboxylic acid with a unique mechanism of action and early clinical studies have reported anti-tumour activity. In a phase II study 32 patients with previously treated advanced breast cancer were given Lonidamine in a daily divided oral dose of 600 mg. Of 28 patients evaluable for response, three (11%) achieved a partial response (4-24+ months) and three (11%) a minor response. Two patients have stable disease (greater than 3 months) and 20 progressed. Toxicity was very mild. Sixteen (53%) of 31 patients had myalgia which lasted a median of 2 weeks. This was investigated with nuclear magnetic resonance spectroscopy in four patients but the changes were unrelated to the degree of myalgia. No other major side-effect was seen, and no dose reduction was required. Lonidamine pharmacokinetics have been investigated in 17 patients 1 month after the start of therapy. Lonidamine was detected in the plasma of all patients, but there was no clear relationship between Lonidamine levels and clinical response or toxicity. Lonidamine appears to be active against advanced breast cancer and its low toxicity would allow combination studies with chemotherapy.

Adenosine Triphosphate↗
PubMed1990

The role of radiotherapy in the management of intracranial meningiomas: the Royal Marsden Hospital experience with 186 patients.

One hundred and eighty-six patients with intracranial meningiomas were treated at the Royal Marsden Hospital between 1963 and 1983 with megavoltage photon irradiation (60Co gamma rays and 6-8 Mv. X rays). Survival parameters were measured from the time of referral for radiotherapy. The 10-year actuarial cause-specific survival was 67% for all cases and the actuarial disease-free survival was 61%. Both malignant and also "aggressive benign" histologies were associated with poor long-term survival. Benign angioblastic meningioma was associated with lower actuarial cause specific and disease-free survival compared with other benign histological sub-groups. Prognosis was related to the extent of initial surgical resection. Of those who underwent subtotal or partial tumor resection with post-operative radiotherapy the 10-year actuarial cause-specific survival was 77%, and in inoperable patients treated by radiotherapy alone it was 46%. Radiotherapy alone resulted in improvement of neurological performance (Karnofsky) in 12 out of the 32 (38%) patients with inoperable disease. The 10-year survival of patients referred for irradiation following "complete" surgical resection was only 34% owing to the high incidence of adverse histological sub-types in this treatment sub-group. Based upon univariate analysis, performance status of less than 60 (Karnofsky) and also age greater than 50 years at the time of referral for radiotherapy were adverse prognostic factors. Multivariate analysis revealed that histological type, extent of surgical resection and performance status at the time of presentation for radiotherapy were independent prognostic variables. However age at the time of referral lost significance as an independent variable when analyzed using this method. Patients undergoing complete surgical resection for the typical benign non-aggressive meningioma do not require adjuvant irradiation. The results of this study support the role of radiotherapy for treatment of incompletely resected and inoperable meningioma of all 3 histological types (benign, "aggressive benign", malignant).

Adolescent↗
PubMed1990

Radioimmunoscintigraphy of orbital metastases from ovarian carcinoma.

Radioimmunoscintigraphy with I-123 labeled monoclonal antibody HMFG1 has been used for imaging primary and metastatic ovarian neoplasms. Uptake of I-123 labeled HMFG1 is reported in a patient with an orbital metastasis from a primary ovarian adenocarcinoma. Radioimmunoscintigraphy may have a role to play in imaging metastatic orbital neoplasms.

Adenocarcinoma↗
PubMed1990

An assessment of the sensitivity of in vivo 31P nuclear magnetic resonance spectroscopy as a means of detecting pH heterogeneity in tumours: a simulation study.

The presence of hypoxia and low pH in tumours is known to influence several treatment modalities including radiotherapy, chemotherapy and hyperthermia. Hypoxic and acidic regions have been demonstrated in tumours using pH and pO2 microelectrodes. The technique has shown marked heterogeneity within individual tumours. A non-invasive measure of intracellular pH is provided by 31P nuclear magnetic resonance (NMR) spectroscopy from determination of the chemical shift of inorganic phosphate, and is being increasingly applied to the study of human tumours in vivo. Based upon the assumption that hypoxic cells are also acidic, we have assessed the ability of a whole-body NMR spectrometer to detect acidic subpopulations within a tumour using simulated tumour spectra. In these simulations the size of the acidic subpopulation, assigned pH values from 5.0 to 7.0, was varied between 5% and 50% of the neutral "control" population. Gaussian noise was added to the simulated spectra giving signal-to-noise ratios for the neutral control inorganic phosphate peak of 3, 5 and 7, which are typical of values encountered in human tumour measurements. From the results of the simulations it seems unlikely that human hypoxic, and presumably acidic, cell fractions, typically 1-15%, will be detected by this method in the presence of signal-to-noise levels characteristic of current equipment. Therefore, whole-body in vivo 31P NMR spectroscopy may fail to identify significant pH heterogeneity within human tumours. Improvements in signal-to-noise and line separation owing to improvements in technique and higher field strength instruments may improve sensitivity to heterogeneous populations.

Cell Hypoxia↗
PubMed1990

Comparison of 5-fluorouracil pharmacokinetics following intraperitoneal and intravenous administration using in vivo 19F magnetic resonance spectroscopy.

Intrahepatic pharmacokinetic studies of 5-Fluorouracil (5 FU) metabolism following intravenous and intraperitoneal administration have been undertaken in four patients using in vivo 19F nuclear magnetic resonance spectroscopy. Following intravenous administration, 5 FU decayed with "half times" ranging from 5 to 17 min. There was considerable variation of 5 FU pharmacokinetics between patients following intraperitoneal administration. Peritoneal contamination by infused 5 FU was considered to be a significant problem in one patient. A technique for providing superficial signal suppression was therefore investigated and its efficacy for excluding signal from the peritoneal space has been demonstrated. Owing to the potential for contamination from peritoneal 5 FU, the accumulation of fluoro-beta-alanine (FBAL) is a more reliable indicator of drug catabolism than the measurement of unlocalized "hepatic" 5 FU. Rapid intrahepatic catabolism of 5 FU to FBAL was demonstrated in all patients. However, there was greater pharmacokinetic variation following intraperitoneal administration than following intravenous administration. Therapeutic implications of intravenous compared with intraperitoneal administration of 5 FU are discussed.

Fluorouracil↗
PubMed1988

Carboplatin (JM8), etoposide (VP16) and thoracic irradiation for small cell lung cancer (S.C.L.C.): an evaluation of lung toxicity.

Carboplatin (JM8) and etoposide (VP16) have demonstrated activity against a range of solid tumours. A retrospective study has looked for evidence of enhanced radiation pneumonitis when these drugs are employed in conjunction with irradiation. Twenty-nine patients with limited disease small cell lung cancer (S.C.L.C.) received JM8 (300 mg/m2) and VP16 (300 mg/m2) at intervals of 3-4 weeks for 4 cycles followed by thoracic irradiation. Twenty-one were evaluated and compared with 21 matched non-S.C.L.C. patients treated by radiotherapy alone. Patients were stratified into three groups according to the radiation dose schedule normalised using Wara's modification of Ellis' formula (n = 0.38, t = 0.06) [28]. Group 1 received less than 1014 rets, Group 2 1015-1250 rets and Group 3 greater than 1250 rets. Radiological pneumonitis was observed in 57% (12/21) of patients receiving combined modality treatment compared to 71% (15/21) of patients receiving radiation alone with evidence of a radiation dose-response relationship for the appearance of pneumonitis in both groups of patients (p greater than 0.1). In conclusion, no enhancement of radiation pneumonitis by carboplatin (JM8) or etoposide (VP16) has been observed.

Adult↗
PubMed1988

Soft-tissue sarcoma: neutrons versus photons for post-operative irradiation.

Between November 1980 and June 1981, 14 patients with soft-tissue sarcoma were entered into a prospective randomized trial comparing the efficacy of megavoltage photon irradiation with cyclotron-generated fast neutrons as post-operative adjuvant therapy. It became apparent that patients whose primary tumours had been treated with very wide excision, in particular by compartmental resection, suffered severe late tissue damage when subsequently irradiated with fast neutrons. It was therefore decided to terminate the trial after only 14 patients had been entered. Unacceptable late tissue damage may result from the therapeutic use of fast neutron irradiation when applied in these circumstances.

Clinical Trials as Topic↗
PubMed1987

Vomiting associated with whole body irradiation.

A study has been made of the patterns of vomiting in 305 patients undergoing total body irradiation before bone marrow transplantation. Vomiting usually begins after a dose of 2 to 3 Gy has been given to the whole body and may persist for up to 12 hours from the start of treatment. There is a recurrence of vomiting after 2 to 5 days. It is infrequent in patients receiving fractionated radiation with fraction sizes of less than 2 Gy, and appears unrelated to cumulative dose after the threshold has been reached. The incidence of vomiting is reduced by limitation of patient movement during radiation and by sedation adequate to keep the patient asleep. It is increased by anxiety and there is a higher incidence in patients aged 10 to 40 than in those aged less than 10 years. Other drugs administered before total body irradiation may affect the incidence. Vomiting can be prevented completely in 50% of patients.

Age Factors↗