Enrollment of patients to clinical trials in haematological cancer in New South Wales: current status, perceived barriers and opportunities for improvement.

BACKGROUND: Enrolment of cancer patients in clinical trials is associated with significant positive outcomes. There are, however, limited Australian data on enrolment of patients with haematological malignancies to clinical trials. AIM: The aim of this study is to document the number of patients with haematological malignancies enrolled on clinical trials in NSW, to establish the barriers to trial recruitment and to examine possible means by which clinical trials participation may be improved. METHODS: Quantitative data on clinical trial accrual were obtained from all sites participating in clinical trials in haematological malignancies in NSW from 2004 to 2007 and were compared with the cancer incidence data for that period. Qualitative data on barriers and strategies for improvement were gathered using semi-structured interviews with clinical trials professionals from throughout NSW. RESULTS: Between 2004 and 2007 there were significant increases in the number of active centres, clinical trials and trial participation, and by 2007, 10.5% of all eligible patients with haematological malignancies in NSW were enrolled in relevant clinical trials. Resource constraints were the greatest perceived barrier to participation, but the success of clinical trials is also challenged by difficulties associated with communication, ethics review, trial coordination, trial design and support for emerging centres. CONCLUSION: While participation in clinical trials in haematological cancer in NSW improved between 2004 and 2007, participation in clinical trials remains suboptimal. The development of specific strategies to address barriers to participation may facilitate increased enrolment and ultimately improve clinical outcomes in patients with haematological malignancies.

Diagnosis and prognosis of breast cancer by magnetic resonance spectroscopy of fine-needle aspirates analysed using a statistical classification strategy.

BACKGROUND: The aim was to develop robust classifiers to analyse magnetic resonance spectroscopy (MRS) data of fine-needle aspirates taken from breast tumours. The resulting data could provide computerized, classification-based diagnosis and prognostic indicators. METHODS: Fine-needle aspirate biopsies obtained at the time of surgery for both benign and malignant breast diseases were analysed by one-dimensional proton MRS at 8.5 Tesla. Diagnostic correlation was performed between the spectra and standard pathology reports, including the presence of vascular invasion by the primary cancer and involvement of the excised axillary lymph nodes. RESULTS: Malignant tissue was distinguished from benign lesions with an overall accuracy of 93 per cent. From the same spectra, lymph node involvement was predicted with an overall accuracy of 95 per cent, and tumour vascular invasion with an overall accuracy of 94 per cent. CONCLUSION: The pathology, nodal involvement and tumour vascular invasion were predicted by computerized statistical classification of the proton MRS spectrum from a fine-needle aspirate biopsy taken from the primary breast lesion.

Fine-needle biopsy specimens of benign breast lesions distinguished from invasive cancer ex vivo with proton MR spectroscopy.

PURPOSE: To determine whether invasive breast cancer can be distinguished from benign lesions with proton magnetic resonance (MR) spectroscopy ex vivo on the basis of altered cellular chemistry. MATERIALS AND METHODS: Two hundred eighteen fine-needle biopsy specimens were obtained in 191 patients undergoing surgery and were analyzed with proton MR spectroscopy. MR spectroscopic and histopathologic findings were compared. RESULTS: Invasive carcinoma produced increased signal at 3.25 ppm, attributable to choline-containing metabolites. Discrimination between invasive carcinoma (n = 82), benign lesions (n = 106), or carcinoma in situ (n = 17) was based on the resonance intensity at 3.25 ppm standardized to the resonance at 3.05 ppm (P < .001). The ratio of peak height intensities of resonances at 3.25 to those at 3.05 ppm was less than 1.7 in 102 of the 106 normal or benign lesions. All carcinoma in situ specimens with comedonecrosis or a microinvasive component (n = 6) were categorized at MR spectroscopy with invasive carcinoma, while others with in situ disease alone were categorized with benign lesions (n = 11). The sensitivity and specificity of MR spectroscopy in fine-needle biopsy specimens in distinguishing benign lesions from invasive cancer were 95% and 96%, respectively. CONCLUSION: Proton MR spectroscopy of fine-needle biopsy specimens provides objective diagnostic information that complements findings of conventional preoperative investigations of breast lesions.

Cancer pathology in the year 2000.

The last one hundred and fifty years has produced the mature and sophisticated discipline of histopathology, yet still leaves the diagnosis of human cancer, by the best available technique, as more art than science. Proton magnetic resonance spectroscopy (1H MRS) ex vivo identifies the chemical markers of established pathobiological disorders within excised biopsies and fine needle aspirates, in particular, those associated with the development and progression of malignant disease. Alterations to cellular chemistry monitored by 1H MRS allows distinction between invasive and pre-invasive lesions of the uterine cervix, and separate truly benign follicular neoplasms from follicular carcinomas on analysis of fine needle aspirates containing as few as 10(6) cells. 1H chemical shift imaging (CSI) determines the spatial location of these chemical changes and provides insight into the chemistry of neoplastic transformation. It is our hypothesis that, by the year 2000, CSI will aid image guided biopsy techniques and that correlation of biopsy histology with in vivo localised 1H MRS data will: (a) lead to improved assessment of the extent of malignant disease and (b) establish the sensitivity and specificity of in vivo 1H MRS for the simultaneous determination of the size, location and neoplastic potential of a tumour mass.

Silicone gel-filled breast implants in women: findings at H-1 MR spectroscopy.

PURPOSE: To evaluate, at hydrogen-1 magnetic resonance (MR) spectroscopy, the effect of implantation time, implant status, and implant removal on the amount of silicone in the liver in women with silicone gel-filled breast prostheses. MATERIALS AND METHODS: The study population included 55 women (39 patients with silicone gel-filled prostheses and seven from whom implants had been removed, and nine control subjects [eight with no implant and one with saline-filled implants]). Stimulated-echo acquisition mode, or STEAM, H-1 MR spectroscopy was performed to determine the concentration of silicone in the liver. Implant status at the time of spectroscopy was diagnosed at MR imaging. RESULTS: Twenty of 39 (51%) women with implants had ruptured prostheses. Resonances associated with the presence of silicone and partially hydrolyzed silicone (0.3 to -0.8 ppm with respect to water at 4.7 ppm) and other resonances that are not yet assigned (-2 to -5 ppm) were detected in 27 (69%) of the 39 women (17 with ruptured implants). Relative signal intensities of the silicone species detected in the liver in these women were found to vary substantially and were not correlated with the status of the implants (P > .70). Silicone resonances were not detected in the livers in the nine control subjects. After implant removal, no resonances between 0.3 and -0.8 ppm were observed in six of seven women, but silicone-related peaks were still detectable in the region of -2 to -5 ppm. CONCLUSION: Proton MR spectra obtained in the liver of women with silicone gel-filled breast implants helped measure silicone exposure.

Enhanced resolution of proton NMR spectra of malignant lymph nodes using magic-angle spinning.

Proton NMR spectroscopy has proven useful in the detection of cancer in lymph node tissue. However, due to the high fat content of this type of tissue, 2D 1H COSY measurements (requiring acquisition times of 4-5 h or longer) are necessary to obtain the spectral information necessary for diagnosis. T2-filtered proton magic-angle spinning (MAS) NMR spectroscopy provides 1D spectra of lymph nodes in approximately 20 min with sufficient spectral resolution allowing for identification of changes in cellular chemistry due to the presence of malignant cells. MAS data from lymph nodes of five control and six rats with mammary adenocarcinoma (R13762) demonstrated increases in the signal intensity of resonances associated primarily with lactate (delta = 4.12 ppm) P < 0.0004, creatines/lysine (delta = 3.04 ppm) P < 0.0032, and glutamate/ glutamine (delta = 2.36 ppm) P < 0.0002 in metastatic compared with normal lymph nodes. The infiltration of lymph nodes by malignant cells is an important prognostic factor for many cancers. The rapid assessment of node tissue without the introduction of sampling errors (inherent in currently employed histological procedures) would allow postoperative therapy decisions to be made more efficiently.

Two-dimensional proton magnetic resonance spectroscopy for tissue characterization of thyroid neoplasms.

We have previously demonstrated that one dimensional (1D) proton (1H) magnetic resonance spectroscopy (MRS) can distinguish normal thyroid tissue from thyroid carcinoma using a spectral ratio of peak intensity at 1.7 ppm/0.9 ppm. Two dimensional (2D) 1H-MRS allows identification of specific molecules that have overlapping peaks in the 1D-MR spectrum. Specimens from 93 consecutive thyroid nodules were examined using 2D 1H-MRS on a Bruker AM-360 wide-bore spectrometer. There was a progressive increase in lipid cross peaks assigned to di-/triglycerides when comparing colloid/hyperplastic nodules to follicular adenoma, and adenoma to carcinoma. A specific cross peak attributable to cholesterol/cholesteryl esters was commonly seen in carcinomas. In contrast, two unassigned cross peaks unique to the thyroid were more prevalent in benign lesions. There was an overall increase in cross peaks attributable to cell surface fucosylation in carcinoma when compared to benign lesions, although the fucose spectral pattern was not specific for cancer. On this basis, a spectral ratio of peak intensity at 2.05 ppm/0.9 ppm more clearly distinguished benign follicular adenoma from carcinoma. 2D 1H-MRS thus identifies chemical changes that allow more specific tissue characterization of thyroid neoplasms.

Diagnosis of follicular thyroid lesions by proton magnetic resonance on fine needle biopsy.

Most thyroidectomies are currently performed for diagnostic purposes. It has been established that proton magnetic resonance spectroscopy (MRS) on excised thyroid tissue can distinguish normal thyroid from invasive carcinomas (P < 0.0001). The purpose of this study was to assess whether the same discrimination could be obtained preoperatively from fine needle biopsy (FNB). This has clinical importance because cytological examination of fine needle aspirates cannot distinguish between benign and malignant follicular thyroid lesions. Here we demonstrate a sensitivity of 95% for proton MRS to correctly identify clinically or histologically proven carcinoma. MRS measurements were made on FNB specimens (containing as few as 10(6) cells) from solitary thyroid nodules. MR assessment of FNB was inconsistent with that of the corresponding tissue in only 6.5% of cases. The discrimination between cancer and normal tissue was based on altered cellular chemistry measured as a one-dimensional spectral ratio of resonances from the amino acid lysine and lipid. Benign follicular lesions were separated into two groups: 67% with a spectral ratio similar to malignant thyroid tumors, and 33% with a spectral ratio comparable to that in normal thyroid tissue. Thus, in contrast with histopathology, MRS offers a method for assessment of FNB of follicular lesions with the potential to identify a biologically benign group, which could avoid thyroid surgery for purely diagnostic purposes.

Computerized consensus diagnosis: a classification strategy for the robust analysis of MR spectra. I. Application to 1H spectra of thyroid neoplasms.

We introduce and apply a new classification strategy we call computerized consensus diagnosis (CCD). Its purpose is to provide robust, reliable classification of biomedical data. The strategy involves the cross-validated training of several classifiers of diverse conceptual and methodological origin on the same data, and appropriately combining their outcomes. The strategy is tested on proton magnetic resonance spectra of human thyroid biopsies, which are successfully allocated to normal or carcinoma classes. We used Linear Discriminant Analysis, a Neural Net-based method, and Genetic Programming as independent classifiers on two spectral regions, and chose the median of the six classification outcomes as the consensus. This procedure yielded 100% specificity and 100% sensitivity on the training sets, and 100% specificity and 98% sensitivity on samples of known malignancy in the test sets. We discuss the necessary steps any classification approach must take to guarantee reliability, and stress the importance of fuzziness and undecidability in robust classification.

Proton magnetic resonance and human thyroid neoplasia. II: Potential avoidance of surgery for benign follicular neoplasms.

Thyroid cancer is rare, but many thyroidectomies continue to be performed simply to exclude a diagnosis of malignancy. The purpose of this study was to determine the potential financial savings associated with the use of proton magnetic resonance analysis of follicular neoplasms. Proton magnetic resonance spectroscopy was performed on tissue obtained at the time of surgery from 98 consecutive solitary or dominant thyroid nodules. Fine-needle biopsies were also performed on operative specimens, and the tissues assessed by proton magnetic resonance; these spectra were then compared with those obtained from tissue specimens. An estimate of potential savings was obtained by comparing the magnetic resonance data with the indications for surgery and pathology on all patients having thyroidectomy over a 10-year period. Proton magnetic resonance spectroscopy was able to distinguish between normal thyroid tissue and invasive thyroid cancer with 100% specificity. Benign follicular adenomas fall into two groups: 44% having a spectral pattern comparable with normal thyroid, and the remaining 56% demonstrating an altered spectral pattern more comparable to the malignant magnetic resonance profile. Proton magnetic resonance spectroscopy on fine-needle biopsy specimens produced spectra similar to those from tissues from the same patient. From a fine-needle biopsy specimen, proton magnetic resonance spectroscopy can identify a group of benign follicular adenomas with spectral profiles akin to those of normal thyroid cells, thus avoiding the need for unnecessary surgical excision. The potential savings in one surgical unit alone were over $1 million in 10 years.

Proton magnetic resonance and human thyroid neoplasia. I: Discrimination between benign and malignant neoplasms.

PURPOSE: Thyroid nodules are very common, yet the vast majority are biologically benign. The extreme difficulty facing the clinician selecting potentially malignant thyroid nodules for surgery was the subject of a recent editorial by Ernest L. Mazzaferri in the American Journal of Medicine (93:359-362, 1992). Here we evaluate the potential of proton magnetic resonance spectroscopy (1H MRS) to provide a solution to this problem. PATIENTS: Thyroid tissue from fifty-three patients undergoing partial or total thyroidectomy for solitary thyroid nodules were assessed by 1H MRS. RESULTS: When compared with the histologic diagnosis, 1H MRS distinguished normal thyroid tissue (n = 8) from invasive papillary (n = 9), anaplastic (n = 1), and medullary (n = 1) carcinomas with P values of < 0.0001, based on altered cellular chemistry. The same magnetic resonance (MR) criteria categorized pathologically proven follicular carcinoma (n = 8) (established as such by the presence of capsular or vascular invasion at the periphery of the tumor, or by the presence of metastases in the patient) with the other thyroid cancers (P < 0.0001). All other "benign" follicular neoplasms (n = 34), including five atypical follicular adenomas, were assessed by the same 1H MRS criteria and found to fit into one of the two above categories, viz. analogous to benign or malignant thyroid tissue. CONCLUSIONS: Proton MRS has the potential to separate out a group of truly benign follicular neoplasms from follicular tumors (both follicular adenomas and follicular carcinomas) that have an atypical follicular pattern on cytologic examination. This is the first report of an objective diagnostic procedure that has the potential to obviate surgical excision in a significant number of patients with benign follicular adenomas, independent of exhaustive histopathologic assessment.

Assessment of human colorectal biopsies by 1H MRS: correlation with histopathology.

Samples (3 mm3) of histopathologically normal (n = 15) and carcinomatous tissue (n = 15) were obtained from colectomy specimens and examined by 1H MRS. A combination of one- and two-dimensional spectra, obtained with appropriate acquisition and processing parameters, provide multiple diagnostic parameters allowing the distinction between normal and carcinomatous tissue. The diagnostic parameters include resonances from choline, choline-based, and other metabolites, cell surface fucosylation, and altered lipid profiles. Tissues histopathologically classified as normal, while remaining distinct from the malignant spectral profile, were found to fit into two categories, one of which had some of the spectral characteristics of malignancy. These results indicate that 1H MRS identifies abnormal colorectal mucosa, which is not morphologically manifest. Such abnormalities have been reported previously to exist in premalignant colorectal tissue by monoclonal antibody studies. Collectively, these results suggest that a clinical study of colorectal biopsies by 1H MRS could provide support for the use of MRS as an adjunct to current pathological procedures.

Magnetic resonance spectroscopy detects cancer in draining lymph nodes.

The spread of cancer cells to draining lymph nodes is an important prognostic factor for many cancers and influences postoperative therapy in patients. Histopathology is used routinely to assess if lymph nodes contain metastases. There are, however, time and resource constraints on the volume of lymph node tissue that can be examined by the pathologist in a routine laboratory (less than 2% of each node), thus major sampling errors are possible. Conventional histopathology also relies on identifying aggregates of malignant cells for a positive diagnosis. Proton (1H) magnetic resonance (MR) spectroscopy can detect chemical changes, specifically increased levels of lactate, choline, fucose and amino acids, in lymph nodes infiltrated by cancer. Increase in lactate indicates the presence of anaerobically respiring cells, whereas choline reports that the cells are replicating. Since MR spectroscopy can identify early infiltration by malignant cells, before cell clusters are visible under the light microscope, it detects micrometastases in lymph nodes missed histopathologically. Furthermore, MR spectroscopy eliminates sampling errors since the entire lymph node is examined.

Cell-surface fucosylation and magnetic resonance spectroscopy characterization of human malignant colorectal cells.

Proton (1H) magnetic resonance spectroscopy (MRS) has been used to distinguish lowly and highly tumorigenic human malignant colorectal cell lines based on differences in lipid, choline, and fucose resonances. The spectral patterns were comparable with those obtained for human colorectal biopsy specimens, indicating that cells grown in vitro are suitable for documenting colorectal tumor biology. For the first time, two-dimensional (2D) correlation spectroscopy (COSY) has been used to assess the fucosylation state on the surface of intact viable cells, and differences were recorded between the highly and lowly tumorigenic cell lines. Four methyl-methine cross-peaks were assigned to covalently linked fucose on the basis of increases in volume following the addition of free fucose. Both cell lines incorporated the same amount of exogenous free fucose as determined chemically, but the COSY spectra indicated that the fucose was distributed differently by each cell line. Of the four sites containing MR-visible bound fucose, one was common to both cell lines, two characteristic of the highly tumorigenic line, and the remaining site unique to the lowly tumorigenic cells. Material released from the highly tumorigenic cells in response to increased cell density was also fucosylated (whereas shed material from lowly tumorigenic cells was not), suggesting a biological role for shed fucosylated antigens in tumor aggression.

Fucose in 1H COSY spectra of plasma membrane fragments shed from human malignant colorectal cells.

The methyl-methine cross peak of bound fucose has been assigned in the COSY spectrum of plasma membrane shed from human malignant colorectal cells. This cross peak (1.33-4.27 ppm), which is superimposed on the methyl-methine cross peak of threonine, was assigned following hydrolysis of the sample. Acid hydrolysis led to a 28 +/- 5% reduction in the intensity of the cross peak and the appearance of the alpha and beta forms of fucose. Chemical analysis confirmed the release of free fucose. Lactate anion, which was not perturbed by the hydrolysis, was used as an internal standard.

Development of the "activated" high resolution 1H MR spectrum in murine T cells and B cells occurs in G1 phase of the cell cycle.

T and B lymphocytes stimulated with mitogens develop 1H MR spectra characteristic of triglycerides in an isotropic environment. These distinctive signals, which are also observed in malignant cells, cannot be suppressed by compounds which inhibit progression through the cell cycle. Cellular proliferation is thus not essential for the development and maintenance of high resolution lipid spectra in activated cells.