Re-188-tricarbonyl tamoxifen as a theranostic radiopharmaceutical for estrogen receptor expressing breast cancers: radiolabeling, characterization and in-vitro cytotoxic assessment.

PURPOSE: Development of a novel theranostic radiopharmaceutical for estrogen receptor, expressing unresectable primary and metastatic breast cancers. METHODS: Tamoxifen was radiolabeled with Rhenium-188 (Re-188) through tricarbonyl core. Radiolabeled complex was characterized by 1proton nuclear magnetic resonance spectroscopy and Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF). Various quality control tests such as sterility, apyrogenicity, and radiochemical purity (RCP) were performed to assess the suitability of the radiopharmaceutical for intravenous administration. In-vitro cell culture studies were performed for cytotoxic assessment. In addition to this, exposure due to different doses of Re-188-tricarbonyl tamoxifen was also calculated. RESULTS: Re-188-tricarbonyl and Re-188-tricarbonyl tamoxifen showed more than 99% RCP. Sample was found to be sterile and pyrogens levels were within the permissible limit. Re-188-tricarbonyl tamoxifen was successfully characterized by MALDI-TOF and 1H-NMR spectroscopy. Re-188 (1.480 MBq) and tamoxifen (0.027 or 0.054 µM) individually showed 36 and 70% cell death, respectively. However, radiolabeled complex (Re-188-tricarbonyl tamoxifen) with the same amount of radioactivity (1.480 MBq) increased the cell death to more than 90% with one-fifth to one-tenth molar concentration of tamoxifen (0.0054 µM). CONCLUSION: Re-188-tricarbonyl tamoxifen can be synthesized in-house in radiopharmacy lab. Radionuclide therapy with Re-188-tricarbonyl tamoxifen can be given using 10 times less amount of tamoxifen as compared to cold tamoxifen.

Effect of Doxorubicin on Squamous Cell Carcinoma of Skin: Assessment by MRI Relaxometry at 4.7T.

Squamous cell carcinoma (SCC) of skin has no standard treatment regimen, resulting in recurrences/metastasis. Although, doxorubicin (Dox), an anthracycline antibiotic has demonstrated some degree of efficacy. Molecular imaging can help in assessment of treatment response and prognosis of SCCs. MRI data showed that spin-spin relaxation (T2) time was longer (138 ± 2 msec) in Dox treated Test-II and there is no significant difference in spin-lattice relaxation (T1) time with respective controls. These findings further corroborated with the histology, proliferation index, apoptotic index, and HMGA1 protein expression. Thus, MRI may be a useful tool for monitoring treatment response noninvasively for skin tumor prognosis.

Pre-operative assessment of residual disease in locally advanced breast cancer patients: A sequential study by quantitative diffusion weighted MRI as a function of therapy.

PURPOSE: The potential of diffusion weighted imaging (DWI) in assessing pathologic response and surgical margins in locally advanced breast cancer patients (n=38) undergoing neoadjuvant chemotherapy was investigated. METHODS: DWI was performed at pre-therapy (Tp0), after I (Tp1) and III (Tp3) NACT at 1.5T. Apparent diffusion coefficient (ADC) of whole tumor (ADCWT), solid tumor (ADCST), intra-tumoral necrosis (ADCNec) was determined. Further, ADC of 6 consecutive shells (5mm thickness each) including tumor margin to outside tumor margins (OM1 to OM5) was calculated and the data analyzed to define surgical margins. RESULTS: Of 38 patients, 6 were pathological complete responders (pCR), 19 partial responders (pPR) and 13 were non-responders (pNR). Significant increase was observed in ADCST and ADCWT in pCR and pPR following therapy. Pre-therapy ADC was significantly lower in pCR compared to pPR and pNR indicating the heterogeneous nature of tumor which may affect drug perfusion and consequently the response. ADC of outside margins (OM1, OM2, and OM3) was significantly different among pCR, pPR and pNR at Tp3 which may serve as response predictive parameter. Further, at Tp3, ADC of outside margins (OM1, OM2, and OM3) was significantly lower compared to that seen at Tp0 in pCR, indicating the presence of residual disease in these shells. CONCLUSION: Pre-surgery information may serve as a guide to define cancer free margins and the extent of residual disease which may be useful in planning breast conservation surgery.

A SHARED study-the benefits and costs of setting up a health research study involving lay co-researchers and how we overcame the challenges.

PLAIN ENGLISH SUMMARY: In the United Kingdom (UK), official bodies such as the Department of Health and research funders such as the National Institute for Health Research support and encourage lay involvement in all stages of research studies. The SHARED study has had substantial patient and public involvement (PPI) from developing the idea to dissemination. The aim of the study has been to develop recommendations led by service users for health and social care professionals to use at hospital discharge and in care planning for people living with memory loss and their carers. This article is about how the study started and the benefits, costs and challenges we encountered as the lead and lay co-researchers. Once we were successful with the grant application, we had to recruit and train the lay co-researchers and obtain various approvals before we could start the project. We had various support from funders, the Research Ethics Committee, lay members of Alzheimer's Society and from the lay co-researchers. However, we encountered some challenges with paying the lay co-researchers and with getting the approval for the co-researchers to interview staff on NHS premises. The challenges were overcome eventually but some aspects of the study changed because of this. We suggest that some changes could be made to the research system which would lead to greater inclusion of the lay co-researchers in research studies and would make the process more straightforward for the research team. ABSTRACT: Background Involving patients and the public in all stages of research has been the focus of the SHARED study. Patient and public involvement (PPI) is an important strategic priority for the Department of Health and funders such as the National Institute for Health Research. The aim of this paper is to describe the benefits, challenges and costs involved in setting up the research study with lay members as part of the research team. The study focused on developing service user-led recommendations for people with memory loss and their carers, on discharge from acute hospital to the community. Methods This began with a discussion of an initial research idea with a lay group of carers and people living with dementia. Once funded, approval was sought from the Research Ethics Committee and NHS Trusts to conduct the research including the active involvement of lay co-researchers. Finally, to recruit, train and pay lay co-researchers in their role. Results The benefits of PPI have included developing ideas which are important to people living with memory loss; support for PPI received from the funders and research ethics committee, high levels of interest from volunteer groups, and lasting enthusiasm from many of the co-researchers. Organisational challenges were met in the requirement for research passports and with payment methods for the co-researchers. Training was beneficial but incurred extra costs for repeated training days. Discussion Overall the benefits outweighed the challenges which were overcome to varying degrees. The lay co-researchers gained membership of a study group and a beneficial partnership developed with the third sector. The biggest challenge was in overcoming the differences in approach to lay co-researchers between NHS Trusts. Organisational culture has been slow to incorporate PPI and this has not yet been fully addressed. It has the potential to delay the start of projects, affect recruitment time, incur extra research costs and disadvantage PPI. Conclusion Buy-in to service user involvement in research studies could be improved by clarifying the requirements for NHS Trust approval and by simplifying the system for financial reimbursement to lay co-researchers. This would improve inclusivity and provide a smoother process for the research team and the co-researchers.

Assessment of changes in brain metabolites in Indian patients with type-2 diabetes mellitus using proton magnetic resonance spectroscopy.

BACKGROUND: The brain is a target for diabetic end-organ damage, though the pathophysiology of diabetic encephalopathy is still not well understood. The aim of the present study was to investigate the effect of diabetes on the metabolic profile of brain of patients having diabetes in comparison to healthy controls, using in-vivo magnetic resonance spectroscopy to get an insight into the pathophysiology of cerebral damages caused due to diabetes. METHODS: Single voxel proton magnetic resonance spectroscopy (1H-MRS) was performed at 1.5 T on right frontal, right parieto-temporal and right parieto-occipital white matter regions of the brain of 10 patients having type-2 diabetes along with 7 healthy controls. Absolute concentration of N-acetylaspartate (NAA), choline (cho), myo-inositol (mI), glutamate (Glu) and glutamine (Gln), creatine (Cr) and glucose were determined using the LC-Model and compared between the two groups. RESULTS: The concentration of N-acetylaspartate was significantly lower in the right frontal [4.35 ±0.69 vs. 5.23 ±0.74; p = 0.03] and right parieto-occipital region [5.44 ±0.52 vs.6.08 ±0.25; p = 0.02] of the brain of diabetics as compared to the control group. The concentrations of glutamate and glutamine were found to be significantly higher in the right frontal region of the brain [7.98 ±2.57 vs. 5.32 ±1.43; P = 0.01] in diabetics. Glucose levels were found significantly elevated in all the three regions of the brain in diabetics as compared to the control group. However, no significant changes in levels of choline, myo-inositol and creatine were observed in the three regions of the brain examined among the two groups. CONCLUSIONS: 1H-MRS analysis indicates that type-2 diabetes mellitus may cause subtle changes in the metabolic profile of the brain. Decreased concentrations of NAA might be indicative of decreased neuronal viability in diabetics while elevated concentrations of Gln and Glu might be related to the fluid imbalance resulting from disruption of glucose homeostasis.

In vivo 1H MRS in the assessment of the therapeutic response of breast cancer patients.

MRI and in vivo MRS have rapidly evolved as sensitive tools for diagnosis and therapeutic monitoring in cancer research. In vivo MRS provides information on tumor metabolism, which is clinically valuable in the diagnosis and assessment of tumor response to therapy for the management of women with breast diseases. Several centers complement breast MRI studies with (1)H MRS to improve the specificity of diagnosis. Malignant breast tissues show elevated water-to-fat ratio and choline-containing compounds (total choline, tCho), and any effect of therapy on tissue viability or metabolism will be manifested as changes in these levels. Sequential (1)H MRS studies have shown significantly reduced tCho levels during the course of therapy in patients who were responders. However, there are challenges in using in vivo MRS because of the relatively low sensitivity in detecting the tCho resonance with decreased lesion size or significant reduction in the tumor volume during therapy. MRS is also technically challenging because of the low signal-to-noise ratio and heterogeneous distribution of fat and glandular tissues in the breast. MRS is best utilized for the diagnosis of focal masses, most commonly seen in patients with ductal-type neoplasms; however, it has limitations in detecting nonfocal masses, such as the linear pattern of tumors seen in invasive lobular carcinoma. Further work is required to assess the clinical utility of quantitative MRS, with the goal of automation, which will reduce the subjectivity currently inherent in both qualitative and semi-quantitative MRS.

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.

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.