Naranamangalam R. Jagannathan

Evaluation of total choline from in-vivo volume localized proton MR spectroscopy and its response to neoadjuvant chemotherapy in locally advanced breast cancer

Results of the proton magnetic resonance spectroscopy carried out on normal, benign breast disease and locally advanced breast cancer patients are presented. The in-vivo MR spectra of malignant breast tissue of patients (n = 67) suffering from infiltrating ductal carcinoma are dominated by the water resonance, while the spectra of the unaffected contralateral breast tissue of these patients are mainly dominated by resonance arising from lipids which is similar to the spectra of normal breast tissue obtained from volunteers (controls, n = 16). In addition to the water and lipid peaks, in majority of the patients (∼80%) the water suppressed spectra showed a resonance at 3.2 ppm due to choline containing compounds (TCho) before treatment. In patients receiving neoadjuvant chemotherapy, absence/reduction in choline was observed in 89% of the patients. TCho was also observed in 2 of 14 benign lesions. The sensitivity and specificity of in-vivo MRS in detecting TCho in malignant tumours was 78% and 86%, respectively. Observation of TCho before treatment and its disappearance (or reduction) after treatment may be a useful indicator of response of locally advanced breast cancer to neoadjuvant chemotherapy.

Longitudinal study of the assessment by MRI and diffusion-weighted imaging of tumor response in patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy.

Measurements of tumor apparent diffusion coefficient (ADC), volume and diameter in assessing the response of patients with locally advanced breast cancer (LABC) (n = 56) undergoing neoadjuvant chemotherapy (NACT) at four time periods (before treatment and after three cycles of NACT) were carried out at 1.5 T using diffusion‐weighted imaging (DWI) and MRI. Ten benign tumors and 15 controls were also investigated. The MR tumor response was compared with the clinical response. Mean ADC before treatment of malignant breast tissue was significantly lower than that of controls, disease‐free contralateral tissue of the patients, and benign lesions, and gradually increased during the course of NACT. Analysis of the percentage change in ADC, volume and diameter after each cycle of NACT between clinical responders and non‐responders showed that the change in ADC after the first cycle was statistically significant compared with volume and diameter, indicating its potential in assessing early response. After the third cycle, the sensitivity for differentiating responders from non‐responders was 89% for volume and diameter and 68% for ADC, and the respective specificities were 50%, 70% and 100%. A sensitivity of 84% (specificity of 60% with an accuracy of 76%) was achieved when all three variables were taken together to predict the response. A cut‐off value of ADC was also calculated using receiver operator characteristics analysis to discriminate between normal, benign and malignant breast tissue. Similarly, a cut‐off value for ADC, volume and diameter was obtained after the second and third cycles of NACT to predict tumor response. The results show that ADC is more useful for predicting early tumor response to NACT than morphological variables, suggesting its potential in effective treatment management. Copyright

Volume localized in vivo proton MR spectroscopy of breast carcinoma: variation of water-fat ratio in patients receiving chemotherapy.

Results are reported on in vivo volume localized proton magnetic resonance spectroscopy (MRS) of patients (n = 44) suffering from carcinoma of the breast, using a bilateral breast surface coil. Localized proton MR spectra of the unaffected contralateral breast of these patients are dominated by resonances arising from fat and are similar to the breast tissue from normal volunteers (controls, n = 13), while in the malignant breast tissues the water resonance dominates. On the other hand, the water suppressed proton MR spectra of malignant breast tissue reveal several metabolites of low concentration including the choline peak around 3.2 ppm and other resonances attributable to purine and pyrimidine nucleotides, in the 8.5 ppm region. Elevated water– fat (W‐F) ratios are measured in the malignant tissues, compared with the normal breast tissue of controls and from the contralateral unaffected breast tissue of the patients (n = 11). In the case of patients receiving chemotherapy resulting in the reduction of primary tumor size, the W‐F ratio shows a statistically significant (P < 0.01) decrease compared with the pre‐therapy value, thus providing a non‐invasive indicator of favourable clinical outcome of neoadjuvant chemotherapy for locally advanced breast cancer. The method provides the potential for non‐invasively monitoring and assessing the response of breast cancer to neoadjuvant chemotherapy. Copyright

Brain metabolite changes in alcoholism: An in vivo proton magnetic resonance spectroscopy (MRS) study

Image-guided, single voxel, localized proton magnetic resonance (MR) spectroscopy was performed to assess the brain metabolite changes in 10 (n = 10) alcoholic patients in the frontal lobe, cerebellum, and thalamus regions. The spectra obtained were characterized by a reduced N-acetyl-aspartate (NAA) to choline (Cho) (p < .01) and NAA to total creatine (Cr + PCr) (p < .01) ratios relative to age-matched (n = 27) controls. These decreased ratios correspond to depleted concentration of the metabolite levels such as NAA and Cho. Reduction of NAA is consistent with the neuronal loss while reduction in Cho suggests significant changes in the membrane lipids of alcoholics.

Effect of melatonin on ischemia reperfusion injury induced by middle cerebral artery occlusion in rats.

Free radicals have been implicated in neuronal injury during ischemia reperfusion in stroke. Therefore, in the present study, melatonin, a potent antioxidant, was studied in male Wistar rats subjected to 2 h of transient middle cerebral artery occlusion. Melatonin (10, 20 and 40 mg/kg i.p.) was administered four times in an animal at the time of middle cerebral artery occlusion, 1 h after middle cerebral artery occlusion, at the time of reperfusion and 1 h after reperfusion. Two hours after reperfusion, rats were euthanized for estimation of oxidative stress markers (malondialdehyde and reduced glutathione). The doses of 20 and 40 mg/kg of melatonin significantly attenuated the raised level of malondialdehyde (287+/-28, 279+/-52 nmol/g wet tissue, respectively) as compared to the levels (420+/-61 nmol/g wet tissue) in vehicle-treated middle cerebral artery-occluded rats. There was an insignificant change in levels of reduced glutathione at these doses (95+/-42, 88.7+/-36 microg/g wet tissue, respectively) as compared to those in the vehicle-treated middle cerebral artery-occluded rats (108.21+/-21 microg/g wet tissue). However, there was an insignificant difference between 20 and 40 mg/kg treated rats. Therefore, the dose of 20 mg/kg i.p. was used to evaluate the neuroprotective effect by using diffusion-weighted imaging (30 min after reperfusion), assessing the neurological deficit (24 h after middle cerebral artery occlusion) and estimating oxidative stress markers (72 h after middle cerebral artery occlusion). In the 20 mg/kg melatonin-treated group, percent ischemic lesion volume on diffusion-weighted imaging was significantly attenuated (9.8+/-3.9) as compared to that in the vehicle-treated group (21.4+/-4.7). The neurological deficit was significantly improved in the melatonin group (1.8+/-0.06) as compared to that in the vehicle-treated (2.9+/-0.38) group. The level of malondialdehyde (321.4+/-31 nmol/g wet tissue) and reduced glutathione (142.6+/-13 microg/g wet tissue) in the melatonin-treated group was also significantly decreased as compared to the level of malondialdehyde (623+/-22 nmol/g wet tissue) and reduced glutathione (226.6+/-19 microg/wet tissue) in the vehicle-treated group. The present study indicates that melatonin has a neuroprotective action in focal ischemia, which may be attributed to its antioxidant property.

Evaluation of Withania somnifera in a middle cerebral artery occlusion model of stroke in rats

1. Stroke causes brain injury in millions of people worldwide each year. Despite the enormity of the problem, there is currently no approved therapy that can reduce infarct size or neurological disability. One of the approaches that can be used in limiting the neurological damage after stroke is the use of prophylactic treatment in patients with a high‐risk of stroke. The present study was undertaken to investigate the effect of the Indian herbal plant Withania somnifera as a prophylactic treatment in the middle cerebral artery (MCA) occlusion model of stroke in rats.

Monitoring the therapeutic response of locally advanced breast cancer patients: Sequential in vivo proton MR spectroscopy study

To evaluate the use of the water‐to‐fat (W‐F) value obtained from in vivo proton (1H) MR spectroscopy (MRS) as a response indicator of cytologically confirmed patients with locally advanced breast cancer (LABC), and to monitor the therapeutic response of such patients to neoadjuvant chemotherapy (NACT)

Assessment of therapeutic response of locally advanced breast cancer (LABC) patients undergoing neoadjuvant chemotherapy (NACT) monitored using sequential magnetic resonance spectroscopic imaging (MRSI).

The potential of total choline (tCho) signal‐to‐noise ratio (SNR) (ChoSNR) and tumor volume in the assessment of tumor response in locally advanced breast cancer (LABC) patients (n = 30) undergoing neoadjuvant chemotherapy (NACT) was investigated using magnetic resonance spectroscopic imaging (MRSI) and conventional MRI at 1.5 T. Experiments were carried out sequentially at four time‐points: prior to therapy and after I, II and III NACT and ChoSNR, and the tumor volume was measured. The MR response was compared with the clinical response. Sequential data of 25 patients were retrospectively analyzed by classifying them as clinical responders and non‐responders. In 14 responders, the pre‐therapy ChoSNR was 7.8 ± 5.1. In 10/14 responders, no choline was observed after III NACT while in the remaining four patients the ChoSNR was reduced to 3.6 ± 1.1 (p < 0.05). Non‐responders showed no statistically significant change in ChoSNR. After III NACT, the tumor volume reduced by 84.0 ± 14.8% in responders. Using receiver operating curve (ROC) analysis, cut‐off values of 53% for ChoSNR and 47.5% for volume were obtained to differentiate responders from non‐responders. The sensitivity to detect responders from non‐responders using ChoSNR was 85.7% with 91% specificity while 100% sensitivity was observed for volume but with reduced specificity of 73%. Our results indicate that ChoSNR may serve as a useful parameter to predict tumor response to NACT with higher specificity compared to volume, suggesting its potential in effective treatment management. Copyright

Metabolism of the colonic mucosa in patients with inflammatory bowel diseases: an in vitro proton magnetic resonance spectroscopy study

Metabolism of the colonic mucosa of patients with ulcerative colitis (UC; n=31) and Crohns disease (CD; n=26) and normal mucosa (control, n=26) was investigated using in vitro high-resolution proton magnetic resonance spectroscopy. Of the 31 UC patients, 20 were in the active phase and 11 were in the remission phase of the disease. Out of 26 CD patients, 20 were in the active phase, while 6 were in the remission phase of the disease. Twenty-nine metabolites were assigned unambiguously in the perchloric acid extract of colonic mucosa. In the active phase of UC and CD, significantly lower (P<or=.05) concentration of amino acids (isoleucine, leucine, valine, alanine, glutamate and glutamine), membrane components (choline, glycerophosphorylcholine and myo-inositol), lactate and succinate were observed compared to normal mucosa of controls. Patients in the active phase of UC and CD also showed increased level of alpha-glucose compared to normal mucosa. Altered level of metabolites indicates decreased protein and carbohydrate metabolism, thereby decreased energy status and deterioration of mucosa integrity during chronic inflammation. In the remission phase of UC and CD, the concentration of most of the metabolites was similar to controls except for lower values of lactate, glycerophosphorylcholine and myo-inositol in UC and Lac in CD. Formate was significantly lower in patients with the active phase of UC compared to patients with the active phase of CD, suggesting the potential of in vitro MRS in the differentiation of these two diseases.

Potential of magnetic resonance spectroscopic imaging in predicting absence of prostate cancer in men with serum prostate-specific antigen between 4 and 10 ng/ml: a follow-up study.

OBJECTIVES Screening for prostate cancer using serum prostate-specific antigen (PSA) determination has a positive predictive value of only 30% to 42% for a PSA level between 4 and 10 ng/mL. Magnetic resonance spectroscopic imaging (MRSI), which identifies cancer on the basis of changes in cellular metabolite levels, might be able to identify patients with noncancerous PSA elevation and help avoid unnecessary biopsies. We tested this hypothesis by evaluating the incidence of prostate cancer in men with a PSA level of 4 to 10 ng/mL and a negative MRSI study. METHODS A total of 155 men underwent a three-dimensional proton MRSI of the prostate before transrectal ultrasound-guided biopsy for clinical indications. MRSI was performed using an endorectal coil on a 1.5-T magnetic resonance scanner. Patients with no voxels positive for malignancy underwent standard sextant biopsy, and additional MRSI-targeted biopsies were obtained in men with suspicious or malignant voxels. Patients with a biopsy negative for cancer underwent repeat serum PSA estimation every 6 months for a minimum of 18 months. RESULTS Of the 155 men, 36 (mean PSA level of 6.47 ng/mL, range 4.25 to 9.9) had no malignant voxels on MRSI. None of them were positive for cancer on biopsy. Of these 36 men, 26 completed at least 18 months (mean 26.9, range 18 to 44) of follow-up. Four patients required repeat biopsies and one, with a persistently elevated PSA level was diagnosed with prostate cancer 29 months after the initial MRSI. CONCLUSIONS The results of our study have shown that prostate biopsy can be deferred in patients with an increased serum PSA of 4 to 10 ng/mL if their MRSI does not show any malignant voxels.