Membranoproliferative glomerulonephritis (MPGN) was recently classified as C3 glomerulopathies (C3G), and immune-complex (IC) mediated MPGN. Dysregulation of the complement alternative pathway, ...driven by acquired and/or genetic defects, plays a pathogenetic role in C3G. However, alternative pathway abnormalities were also found in IC-MPGN. The most common acquired drivers are the C3 nephritic factors (C3NeFs), heterogeneous autoantibodies that stabilize the C3 convertase, C3bBb. C3NeFs are traditionally detected by hemolytic assays based on sheep erythrocyte lysis, which however do not provide a direct molecular estimation of C3bBb formation and decay. We set up a microplate/western blot assay that specifically detects and quantifies C3bBb, and its precursor, the C3 proconvertase C3bB, to investigate the complex mechanistic effects of C3NeFs from patients with primary IC-MPGN (
= 13) and C3G (
= 13). In the absence of properdin, 9/26 patients had C3NeF IgGs stabilizing C3bBb against spontaneous and FH-accelerated decay. In the presence of properdin the IgGs of all but one patient had C3bBb-stabilizing activity. Properdin-independent C3NeFs were identified mostly in DDD patients, while properdin-dependent C3NeFs associated with either C3GN or IC-MPGN and with higher incidence of nephrotic syndrome. When we grouped patients based on our recent cluster analysis, patients in cluster 3, with highly electron-dense intramembranous deposits, low C3, and mostly normal sC5b-9 levels, had a higher prevalence of properdin-independent C3NeFs than patients in clusters 1 and 2. Conversely, about 70% of cluster 1 and 2 patients, with subendothelial, subepithelial, and mesangial deposits, low C3 levels and high sC5b-9 levels, had properdin-dependent C3NeFs. The flexibility of the assay allowed us to get deep insights into C3NeF mechanisms of action, showing that: (1) most C3NeFs bind strongly and irreversibly to C3 convertase; (2) C3NeFs and FH recognize different epitopes in C3 convertase; (3) C3NeFs bind rapidly to C3 convertase and antagonize the decay accelerating activity of FH on newly formed complexes; (4) C3NeFs do not affect formation and stability of the C3 proconvertase. Thus, our study provides a molecular approach to detecting and characterizing C3NeFs. The results highlight different mechanisms of complement dysregulation resulting in different complement profiles and patterns of glomerular injury, and this may have therapeutic implications.
Abstract
Background
Cyclic Vomiting Syndrome (CVS) is a rare functional gastrointestinal disorder, which has a considerable burden on quality of life of both children and their family. Aim of the ...study was to evaluate the diagnostic modalities and therapeutic approach to CVS among Italian tertiary care centers and the differences according to subspecialties, as well as to explore whether potential predictive factors associated with either a poor outcome or a response to a specific treatment.
Methods
Cross-sectional multicenter web-based survey involving members of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) and Italian Society of Pediatric Neurology (SINP).
Results
A total of 67 responses were received and analyzed. Most of the respondent units cared for less than 20 patients. More than half of the patients were referred after 3 to 5 episodes, and a quarter after 5 attacks. We report different diagnostic approaches among Italian clinicians, which was particularly evident when comparing gastroenterologists and neurologists. Moreover, our survey demonstrated a predilection of certain drugs during emetic phase according to specific clinic, which reflects the cultural background of physicians.
Conclusion
In conclusion, our survey highlights poor consensus amongst clinicians in our country in the diagnosis and the management of children with CVS, raising the need for a national consensus guideline in order to standardize the practice.
According to the status of disease, multiple therapies and observational strategies are available for prostate cancer patients, including surgery, external radiotherapy, brachytherapy, hormonal ...therapy, chemotherapy, and radionuclide metabolic therapy, as well as observational programs such as active surveillance and watchful waiting. The path of care for this malignancy is rather complex, involving several health care professionals, and it requires a multidisciplinary approach at specific time points of the disease trajectory. When the health settings cannot provide prostate cancer patients with all the consultations and procedures required for a proper disease management, efforts should be made to implement the path of care, in order to address all patient needs through the collaboration among institutions. This is also in line with Valdagni et al. (1, 2), who stressed the importance of formalizing networks to meet all requirements of a Prostate Cancer Unit. Although multidisciplinary clinics (weekly multidisciplinary first consultations and twice a week observational program followup) and activities (weekly tumor boards) for prostate cancer patients had been running on a regular basis since 2004, the Prostate Cancer Unit at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (INT PCU), was only formalized in 2009, and updated with respect to staff and activities in 2013. In 2014, also with the help of external auditors, bottlenecks and areas with room for improvement were identified (3). Besides organizational and administrative problems, the auditors stressed the lack of robot-assisted surgery and of emergency department (ER). In addition, the uro-oncologists attending the PCU had limited experience with functional and andrologic urology. The Division of Urology at Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico (Policlinico) of Milan, hosting the Specialty in Urology of Milan University, was a referring center for robot-assisted surgery, with extensive experience in urology and andrology. Policlinico had no radiotherapy or brachytherapy unit as well as no experience in the multidisciplinary management of prostate cancer patients and no significant caseload of patients on active surveillance or watchful waiting. In February 2017, INT PCU and with INT become an academic center as Policlinico, and Policlinico formalized an agreement aimed to join efforts, share common diagnostics and therapeutic guidelines to implement the path of care for prostate cancer patients. The collaboration was meant to offer prostate cancer patients referring to both centers a complete path of care, to optimize human and technological resources and meet the standards of a PCU as described in Valdagni et al. (1) and Valdagni et al. (2). INT PCU and Policlinico identified a scientific coordinator and a project manager in each center to supervise the collaboration and check activities and work flows, respectively. Scientific coordinators and project managers agreed on a provisional caseload for every single procedure in each center, which was included in the agreement and was evaluated every 3 months. Moreover, a detailed description of the work flow, the activities, the specialists in charge, and both contact and patient information was prepared and shared among INT PCU, Policlinico clinical and admin team. In detail, INT PCU patients could be referred to Policlinico for functional urologic consultations and procedures, robot-assisted surgery, andrologic consultations, semen cryopreservation, and ER admission. Policlinico patients could be referred to INT PCU for radiotherapy, brachytherapy, observational programs (active surveillance and watchful waiting) and chemotherapy. In addition, Policlinico urologists could attend the INT PCU tumor boards and start working in a MDT setting. On the other hand, INT PCU urologists could assist to robotic radical prostatectomies performed at Policlinico. The agreement refers to the possibility of starting a second phase, focused on clinical, experimental, and translational research projects as well as fund raising and educational activities. Between February 2017 and October 2017, Policlinico referred 17 patients to INT PCU. Nine patients were evaluated by INT PCU radiation oncologists for radiotherapy, 6 patients were discussed in INT PCU tumor board, 1 patient was evaluated by INT PCU medical oncologists. Prostate Specific Membrane Antigen Positron Emission Tomography scan was prescribed to 1 patient, and it was performed in one of the few centers working in this field in Italy, which has had a strong collaboration with INT PCU. PCU INT referred to Policlinico 14 patients. Seven patients were evaluated for urinary symptoms, 2 patients requested the consultation by urologists expert in sexual therapy, 1 patient was interested in robotic surgery, 1 patient referred to Policlinico ER, 1 patient on active surveillance required biopsy in narcosis and 1 patient had macro-hematuria after radiotherapy. Patients referred to INT PCU and Policlinico, and participation of Policlinico urologists at INT PCU tumor boards were recorded by INT PCU project manager, who checked on the data every month as regards caseload and update of patient charts with external consultations. Although both centers paid much attention to detailing work flows and responsibilities and to sharing information with the staff, a few problems occurred. Particularly, patients of both INT PCU and Policlinico referred to the centers without an appointment or documentation for 4 times. One patient, who referred to ER with post-biopsy complications, was seen by clinicians not informed of the formalized collaboration. These inconveniences could be explained by the little promotion that was intentionally acted by INT and Policlinico directors, by the inadequate knowledge of protocols and procedures run by the centers, by the working habits in non-formalized networks, and by the insufficient knowledge of the group members. However, solutions were found and were implemented in order to overcome these barriers. The scientific coordinators spread news of the formalized collaboration with colleagues of other specialties; the project managers organized meetings with clinicians and the administrative staff. Meetings will be scheduled over the forthcoming months to present single activities and protocols. The collaboration proved to be helpful for both INT PCU and Policlinico 1) to complete the path of care for each institution, 2) to improve efficacy and efficiency of diagnostic and therapeutic procedures, 3) to make therapies accessible, 4) to optimize the use of resources, and 5) to promote cross-talk between groups. Patients were happy to have appointments organized and a referral center in touch with one’s clinicians. However, it is important to organize meetings to share thoughts, experience and guidelines between the groups. At the same time, it is fundamental to improve data collection of the cases from each center, to monitor the collaboration and identify potential weaknesses and criticisms that might hamper this synergy. In addition, other areas of interest could be explored and excellences of both centers further appreciated.
It is commonly accepted that oncologic patients benefit from a multidisciplinary management that involves all the professionals participating in the path of care and facilitates timely access to ...therapy, rehab programs and counseling delivered by experienced experts. Multidisciplinary management implements simultaneous care and shifting from a disease-focused to a patient-centered approach in accordance with the policy statement of the European Partnership for Action Against Cancer (EPAAC) (1). This is most true for prostate cancer patients for whom, according to the state of disease, multiple therapies and observational strategies are available and several health care professionals have a role in the disease trajectory. This work describes the experience of Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan (Italy), which formalized the multidisciplinary management of prostate cancer patients running since 2004 in a Prostate Cancer Unit (PCU) and how the PCU affected assistance and care. The organization of multidisciplinary activities organized before (from March 2004, when the Prostate Cancer Program (PCP) was launched, to December 2013, when INT PCU, formalized in 2009, was updated) and after the PCU second formalization (from December 2013 until now) were analyzed. INT PCP redirected translational, preclinical, and clinical research according to diseasefocused shared strategies. In 2004, a multidisciplinary working group focused on writing diagnostic and therapeutic guidelines for evidence-based clinical decisions was established. In 2005, INT PCP started the weekly multidisciplinary clinics for newly referred patients, the weekly follow-up clinics for patients on active surveillance and watchful waiting and the weekly tumor boards. Specialists participating in the PCP were urologists, radiation oncologists, medical oncologists, and uropathologists. Experts in imaging were involved in particular cases, also in consideration of the personal commitment to PCP and the disease. Psychologists, participating as consultants, were supported by a grant from a private donor. In 2009, INT PCU was first formalized, identifying the Chair, the Vice Chair, the clinicians, and the researchers involved in the PCP research and clinical activities. In 2013 and then in 2017, the document was updated in line with Valdagni’s et al. reports on PCUs (2, 3) and in partial response to issues raised by the 2013 external audit (4), with a specific focus on clinical activities, personnel participating, responsibilities and work flows. In details: (i) PCU Chair, Vice Chair, and project manager were nominated. (ii) An agreement was reached between PCU Chair and the Heads of the specialties, concerning the dedication to the PU activities and the time to dedicate (for all the clinicians involved in the path of care). (iii) Clinicians were divided in core team, including specialties that have to attend the PCU activities on a routine basis and non-core team, consisted of specialties involved in specific steps of the disease trajectory; considering that the core team may mutually agree on documented exception to the rule, to optimize resources pathologists participated in selected cases. (iv) PCU clinics were described with respect to organization, clinicians’ participation, and responsibilities. (v) Interdisciplinary collaboration was described in details, including information about the involvement of the non-core team members in the PCU activities. The formalization and update of INT PCU allowed naming the clinicians participating in the PCU upon agreement between the PCU Chair and the directors of the specialties, specifying also the amount of time to be dedicated to the pathology and the PCP activities. Moreover, professionals such as experts in imaging, in nuclear medicine, rehab programs, support, and palliative care were involved, in line with the growing importance of emerging techniques, drugs and procedures. Core and non-core teams were distinguished in order to limit the participation in the PCU activities, thus optimizing effort and resources. In addition, formalization identified the activities and the responsibilities of administrative staff; it described multidisciplinary activities with respect to organization-, participation-, documentation- and communication-related issues, and rationalized the access to clinical case discussion sessions by identifying categories of patients that need to be evaluated multidisciplinarily. Furthermore, formalization facilitated the decisions on reports exiting from multidisciplinary clinics, as well as, the clinical case discussions assessing the participation of multiple professionals. Finally, the importance of periodically reassessing PCU with respect to personnel, activities, and organization, paying particular attention to emerging techniques and procedures and bottlenecks, was appreciated, as well as the importance of having an agreement on evidence-based clinical decisions, coordination of treatments, procedures, professionals and communication within the team and with the patients. Our experience of multidisciplinary approach and PCU activities, however, suggests that there are the following points that need improvement. (i) Although the PCU is formalized, the organizational model is functional, thus determining tasks, roles, and responsibilities, but with limited capacity of Chair and Vice Chair to act on professionals who report on a divisional structure model. (ii) Time for active participation in the PCU should be protected, with the possibility of reassessing it based on unmet needs that may come up from the clinical routine. (iii) Solutions should be found to allow the participation of multiple PCU professionals in the clinical case discussions, making them lively sessions also for educational purposes. Conclusion: The formalization of INT PCU proved helpful 1) to improve the efficacy and efficiency of the multidisciplinary organizational model, 2) to optimize resources and procedures, 3) to facilitate interprofessional collaboration and synergy. However, efforts should be made by Admin as well as experts in organization, management, and human resources to overcome the limitation of functional organization. Solutions to boost motivation and permit the participation of professionals in the clinical case discussions as often as possible should also be found. Activities and participation should be checked on a routine basis to identify bottlenecks and criticisms that might hinder the multidisciplinary synergy.
After the launch of the Prostate Cancer Programme in September 2004, the clinical management of prostate cancer (PCa) patients at Fondazione IRCCS Istituto Nazionale dei Tumori (INT), in Milan, ...became multidisciplinary, and multidisciplinary consultations and clinical case discussions were organized on a weekly routine basis. From the start it was clear that the model needed to be adaptable to meet new clinical and organizational needs. Magnani et al. (1) referred to the 2004-2011 experience. This abstract describes the initial multidisciplinary consultations and the clinical case discussions in terms of numbers, organization and access and the changes introduced in 2012-2017. From March 2005 to October 2017 an average of 350 multidisciplinary consultations per year were performed on a weekly basis. An urologist, a radiation oncologist and a psychologist were seeing 8 patients with a PCa diagnosis in any state of disease who refer to INT for the first time. Medical oncologists are also involved in advanced or metastatic PCa. From March 2005 to October 2017, an average of 340 clinical case discussions per year was performed on a weekly basis. At least one representative for urology, radiation oncology, medical oncology, the research nurse and the project manager participated mandatorily, while other professionals (for example imaging specialists, uropathologists, palliative care specialists) were called in on particular cases. Prostate Cancer Unit (PCU) was formalized in 2009 and updated in 2013. In February 2017 the collaboration between INT PCU and Urology Division at Policlinico, Milan, was made official to implement the PCa path of care of both institutes, also in line with Valdagni’s et al. papers on PCU (2, 3). Magnani et al. reported on INT multidisciplinary activities from March 2005 to March 2011 (1). Since 2012, an increase in very low-/lowrisk class patients (61.5% vs. 51%) and a decrease in highrisk (13% vs. 26%) and metastatic (1.5% vs. 5%) patients were observed, compared to the period 2005-2011. The percentage of intermediate-risk patients was maintained (26% vs. 24%). 9.5% of the patients had already received a PCa treatment before visit. The following changes were introduced in the organizational model: (i) Due to the lack of resources (psychologists are supported by a grant from a private donor) the individual counselling meeting with the psychologist after the first multidisciplinary consultation was interrupted in 2014. Patients who seemed to potentially benefit from psychological support were invited to meet the psychologist in the afternoon or schedule an appointment. (ii) Selection of cases for clinical case discussions: In the 2005-2011 period, all cases examined in the multidisciplinary clinic were discussed in the weekly tumour board to evaluate adherence to guidelines, check on the quality of the decisions formulated in the clinic, to tailor therapeutic or observational strategies and to facilitate the interdisciplinary collaboration and education. After carefully analyzing the data on the clinical case discussions and the changes applied to the decisions taken in the clinic, in 2014 we chose not to discuss all the cases examined in the first multidisciplinary consultations. Since 2014 clinical case discussions were mainly focused on patients who, after the multidisciplinary consultations, had to complete staging before therapeutic and observational options could be proposed and patients on active surveillance or watchful waiting with borderline situations with respect to institutional protocols. (iii) Since 2015 a research nurse has participated in the clinical case discussions, thus enabling the selection of patients to be included in clinical trials. In addition, the nurse became the contact person between clinicians and patients and follows up after the discussion to schedule appointments, to plan future steps and to inform patients and clinicians. (iv) The formalization of the PCU identified and named the specialists involved in the PCa path of care divided in core and non-core team, described the PCa dedicated activities and the participation in the PCU multidisciplinary activities. As regards the clinical case discussions, professionals of the non-core team needed on a particular case were receiving a request from the PCU Secretary and upon their confirmation the case was scheduled. (v) Since the formalization of INT PCUPoliclinico collaboration, urologists from Policlinico participate in the clinical case discussions presenting their cases. Multidisciplinary approach has proven successful to address PCa complexity. A flexible organizational model is necessary to meet new scenarios (both clinical and organizational). Monitoring is mandatory to detect bottle necks and criticisms.
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