Image-derived input functions from dynamic O-15-water PET scans using penalised reconstruction

BACKGROUND: Quantitative positron emission tomography (PET) scans of the brain typically require arterial blood sampling but this is complicated and logistically challenging. One solution to remove the need for arterial blood sampling is the use of image-derived input functions (IDIFs). Obtaining accurate IDIFs, however, has proved to be challenging, mainly due to the limited resolution of PET. Here, we employ penalised reconstruction alongside iterative thresholding methods and simple partial volume correction methods to produce IDIFs from a single PET scan, and subsequently, compare these to blood-sampled input curves (BSIFs) as ground truth. Retrospectively we used data from sixteen subjects with two dynamic 15O-labelled water PET scans and continuous arterial blood sampling: one baseline scan and another post-administration of acetazolamide. RESULTS: IDIFs and BSIFs agreed well in terms of the area under the curve of input curves when comparing peaks, tails and peak-to-tail ratios with R2 values of 0.95, 0.70 and 0.76, respectively. Grey matter cerebral blood flow (CBF) values showed good agreement with an average difference between the BSIF and IDIF CBF values of 2% ± and a coefficient of variation (CoV) of 7.3%. CONCLUSION: Our results show promising results that a robust IDIF can be produced for dynamic 15O–water PET scans using only the dynamic PET scan images with no need for a corresponding MRI or complex analytical techniques and thereby making routine clinical use of quantitative CBF measurements with 15O–water feasible

Impact of previous disease-modifying treatment on safety and efficacy in patients with MS treated with AHSCT

Background Autologous haematopoietic stem cell transplantation (AHSCT) is a highly effective treatment for multiple sclerosis (MS). The impact of previous long-lasting disease-modifying treatments (DMT) for safety and efficacy of AHSCT is unknown. Objective To explore whether previous DMTs with long-lasting effects on the immune system (anti-CD20 therapy, alemtuzumab and cladribine) affect treatment-related complications, long-term outcome and risk of new MS disease activity in patients treated with AHSCT. Methods Retrospective observational study of 104 relapsing remitting patients with MS treated by AHSCT in Sweden and Norway from 2011 to 2021, grouped according to the last DMT used ≤6 months prior to AHSCT. The primary outcomes were early AHSCT-related complications (mortality, neutropenic fever and hospitalisation length), long-term complications (secondary autoimmunity) and proportion of patients with No Evidence of Disease Activity (NEDA-3 status): no new relapses, no MRI activity and no disease progression during the follow-up. Results The mean follow-up time was 39.5 months (range 1–95). Neutropenic fever was a common AHSCT-related complication affecting 69 (66%) patients. There was no treatment-related mortality. During the follow-up period, 20 patients (19%) were diagnosed with autoimmunity. Occurrence of neutropenic fever, hospitalisation length or secondary autoimmunity did not vary dependent on the last DMT used prior to AHSCT. A total of 84 patients (81%) achieved NEDA-3 status, including all patients (100%) using rituximab, alemtuzumab or cladribine before AHSCT. Conclusion This study provides level 4 evidence that AHSCT in patients previously treated with alemtuzumab, cladribine or rituximab is safe and efficacious.publishedVersio

In search of lost disease : Clinical, qualitative and imaging studies to investigate long-term effects of autologous haematopoietic stem cell transplantation for multiple sclerosis

With the introduction of autologous haematopoietic stem cell transplantation (AHSCT) for the treatment of multiple sclerosis (MS), there are now individuals living without experiencing disease activity of MS. Are they cured?  There is a need for terminology to describe the state of these individuals. To address this and to report the ten-year outcomes of the first ten persons treated with AHSCT for MS at our centre, we conducted tests involving six different outcome measures to encompass the inflammatory (new clinical relapses, new MRI lesions, intrathecal antibody production) and degenerative (clinical progression, elevated intrathecal levels of neurofilament light protein, presence of callosal atrophy) aspects of the disease. Half of the participants achieved ‘sustained complete remission’ (normal values in all parameters, excluding intrathecal measurements), and three ‘resolved disease’ by displaying standard values across all measures. This terminology can be used when communicating successful treatment outcomes, and ‘resolved disease’ might serve as a working definition of cure. How did one perceive oneself, one’s health, and one’s diagnosis ten years after AHSCT? In this qualitative interview study, the lived experience of the same persons was explored and analysed with qualitative content analysis. The treatment symbolised a transition from a life dominated by uncertainty to a state of health and normality. The participants shared their experience of now feeling healthy, and some even reported not having MS anymore. They expressed a desire for objective criteria to affirm their health status. Impaired cerebral blood flow has been linked to progressive MS. The third study was a case-control study examining CBF and cerebrovascular reactivity (CVR) in individuals with secondary progressive MS, healthy controls, and persons treated with AHSCT from the previous studies. CBF was measured using positron emission tomography with 15O-water. CBF was diminished in individuals with progressive MS compared to the healthy controls. In contrast, CBF in the AHSCT group did not differ significantly from healthy controls. CVR was not impaired in progressive MS patients, suggesting an opportunity for therapeutic intervention with a vasodilating agent. The fourth study was a case-control study assessing factors associated with a favourable response to COVID-19 vaccination in persons with rituximab and MS. B cells emerged as the sole factor influencing antibody production. Consequently, pre-vaccination B-cell measurement was advised to enhance the likelihood of an effective humoral immune response

In search of lost disease : Clinical, qualitative and imaging studies to investigate long-term effects of autologous haematopoietic stem cell transplantation for multiple sclerosis

With the introduction of autologous haematopoietic stem cell transplantation (AHSCT) for the treatment of multiple sclerosis (MS), there are now individuals living without experiencing disease activity of MS. Are they cured?  There is a need for terminology to describe the state of these individuals. To address this and to report the ten-year outcomes of the first ten persons treated with AHSCT for MS at our centre, we conducted tests involving six different outcome measures to encompass the inflammatory (new clinical relapses, new MRI lesions, intrathecal antibody production) and degenerative (clinical progression, elevated intrathecal levels of neurofilament light protein, presence of callosal atrophy) aspects of the disease. Half of the participants achieved ‘sustained complete remission’ (normal values in all parameters, excluding intrathecal measurements), and three ‘resolved disease’ by displaying standard values across all measures. This terminology can be used when communicating successful treatment outcomes, and ‘resolved disease’ might serve as a working definition of cure. How did one perceive oneself, one’s health, and one’s diagnosis ten years after AHSCT? In this qualitative interview study, the lived experience of the same persons was explored and analysed with qualitative content analysis. The treatment symbolised a transition from a life dominated by uncertainty to a state of health and normality. The participants shared their experience of now feeling healthy, and some even reported not having MS anymore. They expressed a desire for objective criteria to affirm their health status. Impaired cerebral blood flow has been linked to progressive MS. The third study was a case-control study examining CBF and cerebrovascular reactivity (CVR) in individuals with secondary progressive MS, healthy controls, and persons treated with AHSCT from the previous studies. CBF was measured using positron emission tomography with 15O-water. CBF was diminished in individuals with progressive MS compared to the healthy controls. In contrast, CBF in the AHSCT group did not differ significantly from healthy controls. CVR was not impaired in progressive MS patients, suggesting an opportunity for therapeutic intervention with a vasodilating agent. The fourth study was a case-control study assessing factors associated with a favourable response to COVID-19 vaccination in persons with rituximab and MS. B cells emerged as the sole factor influencing antibody production. Consequently, pre-vaccination B-cell measurement was advised to enhance the likelihood of an effective humoral immune response

Experiences of being treated with autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: A qualitative interview study.

BackgroundAutologous haematopoietic stem cell transplantation (AHSCT) is increasingly used as a treatment for aggressive multiple sclerosis (MS) and has the potential to induce long-term remission and resolution of disease activity. Despite the extensive research on treatment outcome after AHSCT, the experience of living with MS after AHSCT has not been previously described in the scientific literature. The aim of this study was to explore long-term lived experience of people with MS treated with AHSCT.Methods and findingsTo exclude selection bias, all persons treated with AHSCT for MS at Uppsala University Hospital, Sweden, between 2004 and 2007 (n = 10), were asked to participate in the study, and all accepted. Open-ended interviews were conducted, digitally recorded, transcribed verbatim, and then subjected to qualitative content analysis with an inductive approach. Five main themes emerged from the interviews: (I) being diagnosed with MS-an unpredictable existence; (II) a new treatment-a possibility for a new life; (III) AHSCT-a transition; (IV) reclaiming life; and (V) a bright future accompanied by insecurity. AHSCT was described by the participants in terms of a second chance and an opportunity for a new life. The treatment became a transition from a state of illness to a state of health, enabling a previous profound uncertainty to wane and normality to be restored. Although participants of different age and sex were included, the main limitation of this study is the relatively small number of participants. Also, the inclusion of persons from one centre alone could restrict transferability of the results.ConclusionsThe results give a first insight into lived experience following a highly effective induction treatment for MS, and the experience of not having MS anymore. Underpinned by previously described outcome following AHSCT, the results of this study challenge the current view on MS as a chronic disease with no possible cure

Anti-Müllerian hormone and pregnancy after autologous hematopoietic stem cell transplantation for multiple sclerosis

Autologous hematopoietic stem cell transplantation (AHSCT) has been approved for multiple sclerosis (MS) in many European countries. A large proportion of patients are women of child-bearing age. For them, AHSCT may have negative consequences for reproductive health, since the ovaries are particularly susceptible to alkylating agents. Anti-Müllerian hormone (AMH) reflects the ovarian reserve and has been suggested as a potential biomarker of fertility in women. The aim of this study was to investigate AMH levels in relation to age and reproductive potential in MS patients treated with AHSCT. The study cohort comprised 38 female patients, aged 20–44 years, who underwent AHSCT for MS using a cyclophosphamide (200 mg/kg)/rabbit—anti-thymocyte globulin (6 mg/kg) conditioning regimen between 2013–2020. Clinal follow-up visits were made 3 months after AHSCT and then yearly. AMH was analysed in blood samples. The median age at transplantation was 28 years (interquartile range, IQR 25–33). The median AMH concentration was 23 pmol/l at baseline (IQR 6.0–30), 0.5 pmol/l at 3 months (IQR 0–1.5) and 1.1 pmol/l at 2 years (IQR 0–2.9). A multiple linear regression model was used to determine if age and/or AHSCT influenced AMH values; both significantly did (age, -0.21 per year, p = 0.018; AHSCT -19, p <0.0001). Seven women became pregnant, six spontaneously and one both spontaneously and with IVF. One patient underwent an abortion, all other pregnancies led to live births. Six of the women became pregnant despite low or very low post-AHSCT serum concentrations of AMH, suggesting that low serum AMH concentrations do not necessarily reflect impaired fertility in patients treated with high-dose cyclophosphamide

Anti-Müllerian hormone and pregnancy after autologous hematopoietic stem cell transplantation for multiple sclerosis

Autologous hematopoietic stem cell transplantation (AHSCT) has been approved for multiple sclerosis (MS) in many European countries. A large proportion of patients are women of child-bearing age. For them, AHSCT may have negative consequences for reproductive health, since the ovaries are particularly susceptible to alkylating agents. Anti-Müllerian hormone (AMH) reflects the ovarian reserve and has been suggested as a potential biomarker of fertility in women. The aim of this study was to investigate AMH levels in relation to age and reproductive potential in MS patients treated with AHSCT. The study cohort comprised 38 female patients, aged 20–44 years, who underwent AHSCT for MS using a cyclophosphamide (200 mg/kg)/rabbit—anti-thymocyte globulin (6 mg/kg) conditioning regimen between 2013–2020. Clinal follow-up visits were made 3 months after AHSCT and then yearly. AMH was analysed in blood samples. The median age at transplantation was 28 years (interquartile range, IQR 25–33). The median AMH concentration was 23 pmol/l at baseline (IQR 6.0–30), 0.5 pmol/l at 3 months (IQR 0–1.5) and 1.1 pmol/l at 2 years (IQR 0–2.9). A multiple linear regression model was used to determine if age and/or AHSCT influenced AMH values; both significantly did (age, -0.21 per year, p = 0.018; AHSCT -19, p <0.0001). Seven women became pregnant, six spontaneously and one both spontaneously and with IVF. One patient underwent an abortion, all other pregnancies led to live births. Six of the women became pregnant despite low or very low post-AHSCT serum concentrations of AMH, suggesting that low serum AMH concentrations do not necessarily reflect impaired fertility in patients treated with high-dose cyclophosphamide

Image-derived input functions from dynamic 15O–water PET scans using penalised reconstruction

Background: Quantitative positron emission tomography (PET) scans of the brain typically require arterial blood sampling but this is complicated and logistically challenging. One solution to remove the need for arterial blood sampling is the use of image-derived input functions (IDIFs). Obtaining accurate IDIFs, however, has proved to be challenging, mainly due to the limited resolution of PET. Here, we employ penalised reconstruction alongside iterative thresholding methods and simple partial volume correction methods to produce IDIFs from a single PET scan, and subsequently, compare these to blood-sampled input curves (BSIFs) as ground truth. Retrospectively we used data from sixteen subjects with two dynamic 15O-labelled water PET scans and continuous arterial blood sampling: one baseline scan and another post-administration of acetazolamide. Results: IDIFs and BSIFs agreed well in terms of the area under the curve of input curves when comparing peaks, tails and peak-to-tail ratios with R2 values of 0.95, 0.70 and 0.76, respectively. Grey matter cerebral blood flow (CBF) values showed good agreement with an average difference between the BSIF and IDIF CBF values of 2% ± and a coefficient of variation (CoV) of 7.3%. Conclusion: Our results show promising results that a robust IDIF can be produced for dynamic 15O–water PET scans using only the dynamic PET scan images with no need for a corresponding MRI or complex analytical techniques and thereby making routine clinical use of quantitative CBF measurements with 15O–water feasible

Examples of the steps of the analyses from the interview with Daniel: Meaning units, condensation, interpretation of latent meaning, subtheme, and theme.

Examples of the steps of the analyses from the interview with Daniel: Meaning units, condensation, interpretation of latent meaning, subtheme, and theme.</p

Demographic, clinical and interview data of the participants.

Demographic, clinical and interview data of the participants.</p