Immunosuppression withdrawal in living-donor renal transplant recipients following induction with antithymocyte globulin and rituximab: Results of a prospective clinical trial.

Durable tolerance in kidney transplant recipients remains an important but elusive goal. We hypothesized that adding B cell depletion to T cell depletion would generate an immune milieu postreconstitution dominated by immature transitional B cells, favoring tolerance. The Immune Tolerance Network ITN039ST Research Study of ATG and Rituximab in Renal Transplantation was a prospective multicenter pilot study of live donor kidney transplant recipients who received induction with rabbit antithymocyte globulin and rituximab and initiated immunosuppression (IS) withdrawal (ISW) at 26 weeks. The primary endpoint was freedom from rejection at 52 weeks post-ISW. Six of the 10 subjects successfully completed ISW. Of these 6 subjects, 4 restarted immunosuppressive medications due to acute rejection or recurrent disease, 1 remains IS-free for over 9 years, and 1 was lost to follow-up after being IS-free for 42 weeks. There were no cases of patient or graft loss. CD19+ B cell frequencies returned to predepletion levels by 26 weeks posttransplant; immunoglobulin D+CD27--naïve B cells predominated. In contrast, memory cells dominated the repopulation of the T cell compartment. A regimen of combined B and T cell depletion did not generate the tolerogenic B cell profile observed in preclinical studies and did not lead to durable tolerance in the majority of kidney transplant recipients.

Early allogeneic immune modulation after establishment of donor hematopoietic cell-induced mixed chimerism in a nonhuman primate kidney transplant model.

Background: Mixed lymphohematopoietic chimerism is a proven strategy for achieving operational transplant tolerance, though the underlying immunologic mechanisms are incompletely understood. Methods: A post-transplant, non-myeloablative, tomotherapy-based total lymphoid (TLI) irradiation protocol combined with anti-thymocyte globulin and T cell co-stimulatory blockade (belatacept) induction was applied to a 3-5 MHC antigen mismatched rhesus macaque kidney and hematopoietic cell transplant model. Mechanistic investigations of early (60 days post-transplant) allogeneic immune modulation induced by mixed chimerism were conducted. Results: Chimeric animals demonstrated expansion of circulating and graft-infiltrating CD4+CD25+Foxp3+ regulatory T cells (Tregs), as well as increased differentiation of allo-protective CD8+ T cell phenotypes compared to naïve and non-chimeric animals. In vitro mixed lymphocyte reaction (MLR) responses and donor-specific antibody production were suppressed in animals with mixed chimerism. PD-1 upregulation was observed among CD8+ T effector memory (CD28-CD95+) subsets in chimeric hosts only. PD-1 blockade in donor-specific functional assays augmented MLR and cytotoxic responses and was associated with increased intracellular granzyme B and extracellular IFN-γ production. Conclusions: These studies demonstrated that donor immune cell engraftment was associated with early immunomodulation via mechanisms of homeostatic expansion of Tregs and early PD-1 upregulation among CD8+ T effector memory cells. These responses may contribute to TLI-based mixed chimerism-induced allogenic tolerance.

Helical TomoTherapy Total Lymphoid Irradiation and Hematopoietic Cell Transplantation for Kidney Transplant Tolerance in Rhesus Macaques.

Development of a post-transplant kidney transplant tolerance induction protocol involving a novel total lymphoid irradiation (TLI) conditioning method in a rhesus macaque model is described. We examined the feasibility of acheiving tolerance to MHC 1-haplotype matched kidney transplants by establishing a mixed chimeric state with infusion of donor hematopoietic cells (HC) using TomoTherapy TLI. The chimeric state was hypothesized to permit the elimination of all immunosuppressive (IS) medications while preserving allograft function long-term without development of graft-versus-host-disease (GVHD) or rejection. An experimental group of 11 renal transplant recipients received the tolerance induction protocol and outcomes were compared to a control group (n = 7) that received the same conditioning but without donor HC infusion. Development of mixed chimerism and operational tolerance was accomplished in two recipients in the experimental group. Both recipients were withdrawn from all IS and continued to maintain normal renal allograft function for 4 years without rejection or GVHD. None of the animals in the control group achieved tolerance when IS was eliminated. This novel experimental model demonstrated the feasibility for inducing of long-term operational tolerance when mixed chimerism is achieved using a TLI post-transplant conditioning protocol in 1-haplotype matched non-human primate recipients of combined kidney and HC transplantation.

Master protocol to assess the long-term safety in kidney transplant recipients who previously received Medeor's cellular immunotherapy products: the MDR-105-SAE.

BACKGROUND: Immunosuppression in transplantation continues to be associated with a multitude of adverse effects. Induction of immune tolerance may be a viable strategy to reduce dependence on immunosuppression. Various trials are currently underway to assess the efficacy of this strategy. However, long-term safety data for these immune tolerance regimes has yet to be established. METHODS/DESIGN: At the completion of primary follow-up of various Medeor kidney transplant studies, subjects receiving cellular immunotherapy products will be followed annually as per protocolized schedule for up to an additional 84 months (7 years) to evaluate long-term safety. Long-term safety will be assessed by summarizing incidence of serious adverse events, adverse events leading to study withdrawal and hospitalization rates. DISCUSSION: This extension study will be an important step in evaluating safety issues pertaining to immune tolerance regimens, long-term effects of which are largely unknown. These data are essential for furthering an unrealized goal of kidney transplantation- graft longevity without the adverse effects from long-term immunosuppression. The study design utilizes the methodology of a master protocol, wherein multiple therapies can be assessed simultaneously with accompanied gathering of long-term safety data.

Predictors of distress associated with altered appearance and function in people treated surgically for oral cancers: a cross-sectional study.

This cross-sectional study was performed to examine sources of variation in distress associated with altered appearance and fundamental functions in oral cancer patients at 2 months, 12-15 months, 24-36 months, and ≥ 5 years post-definitive treatment. Eligible patients completed six scales from the FACE-Q Head and Neck Cancer Module. Pre-specified regression models were used to examine sources of variation in study outcomes for 145 patients. Patient self-reports indicated that distress associated with altered appearance and fundamental functions was highly variable, and distress was present beyond 5 years post-definitive treatment in some patients. Associations between distress scores and time post-definitive treatment, reconstructive surgery, and adjuvant therapy were not statistically significant. There was, however, moderate to strong evidence against the null hypothesis of no association between eating distress scores and sex, primary cancer site, and T-stage; smiling distress scores and age and primary cancer site; appearance distress scores and geographical remoteness and primary cancer site; and speaking distress scores and primary cancer site. Primary cancer site was the only significant independent predictor of multiple distress scores. These findings suggest that predicting the psychological impact of oral cancer treatment remains a challenge for the multidisciplinary team. Screening and interventions for psychological distress are essential beyond the preoperative and acute care settings.

Post-pancreatic transplant enteric leaks: The role of the salvage operation.

Enteric drainage in pancreas transplantation is complicated by an enteric leak in 5%-8%, frequently necessitating pancreatectomy. Pancreatic salvage outcomes are not well studied. Risk factors for enteric leak were examined and outcomes of attempted graft salvage were compared to immediate pancreatectomy. Pancreas transplants performed between 1995 and 2018 were reviewed. Donor, recipient, and organ variables including demographics, donor type, ischemic time, kidney donor profile index, and pancreas donor risk index were analyzed. Among 1153 patients, 33 experienced enteric leaks (2.9%). Donors of allografts that developed leak were older (37.9y vs. 29.0y, p = .001), had higher KDPI (37% vs. 24%, p < .001), higher pancreas donor risk index (1.83 vs. 1.32, p < .001), and longer cold ischemic time (16.5 vs. 14.8 h, p = .03). Intra-abdominal abscess and higher blood loss decreased the chance of successful salvage. Enteric leak increased 6-month graft loss risk (HR 13.9[CI 8.5-22.9], p < .001). However, 50% (n = 12) of allografts undergoing attempted salvage survived long-term. After 6 months of pancreas graft survival, salvage and non-leak groups had similar 5-year graft survival (82.5% vs. 81.5%) and mortality (90.9% vs. 93.5%). Enteric leaks remain a challenging complication. Pancreatic allograft salvage can be attempted in suitable patients and accomplished in 50% of cases without significantly increased graft failure or mortality risk.

Robust engraftment of fetal nonhuman primate CD34-positive cells in immune-deficient mice.

Nonhuman primates (NHPs) represent one of the most important models for preclinical studies of novel biomedical interventions. In contrast with small animal models, however, widespread utilization of NHPs is restricted by cost, logistics, and availability. Therefore, we sought to develop a translational primatized mouse model, akin to a humanized mouse, to allow for high-throughput in vivo experimentation leveraged to inform large animal immunology-based studies. We found that adult rhesus macaque mobilized blood (AMb) CD34+-enriched hematopoietic stem and progenitor cells (HSPCs) engrafted at low but persistent levels in immune-deficient mice harboring transgenes for human (NHP cross-reactive) GM-CSF and IL3, but did not in mice with wild-type murine cytokines lacking NHP cross-reactivity. To enhance engraftment, fetal liver-derived HSPCs were selected as the infusion product based on an increased CD34hi fraction compared with AMb and bone marrow. Coupled with cotransplantation of rhesus fetal thymic fragments beneath the mouse kidney capsule, fetal liver-derived HSPC infusion in cytokine-transgenic mice yielded robust multilineage lymphohematopoietic engraftment. The emergent immune system recapitulated that of the fetal monkey, with similar relative frequencies of lymphocyte, granulocyte, and monocyte subsets within the thymic, secondary lymphoid, and peripheral compartments. Importantly, while exhibiting a predominantly naïve phenotype, in vitro functional assays demonstrated robust cellular activation in response to nonspecific and allogenic stimuli. This primatized mouse represents a viable and translatable model for the study of hematopoietic stem cell physiology, immune development, and functional immunology in NHPs. Summary Sentence: Engraftment of rhesus macaque hematopoietic tissues in immune-deficient mice yields a robust BLT/NeoThy-type primatized mouse model for studying nonhuman primate hematopoiesis and immune function in vivo.

Early Increases in Posttransplant Pancreatic Enzymes Are Associated With Surgical Complications But Not Graft Failure Among Pancreas Transplant Recipients.

OBJECTIVES: This study aimed to find the association between immediate postoperative increases in pancreatic enzymes and posttransplant complications among pancreas transplant recipients (PTRs). METHODS: We analyzed all PTRs transplanted at the University of Wisconsin between June 2009 and September 2018. Enzyme levels were presented as a ratio of absolute numbers to the upper limit of normal value, with value >1 considered as abnormal. We specifically evaluated bleeding, fluid collections, and thrombosis complications based on the amylase or lipase ratios on day 1 (Amylase1, Lipase1) and maximum ratios within 5 days of transplant (Amylasemax, Lipasemax). For early complications, we focused on technical complications that occurred within 90 days of transplant. For long-term outcomes, we assessed patient and graft survival, and rejections. RESULTS: There were a total of 443 PTRs, 287 were simultaneous pancreas and kidney recipients, and 156 were solitary pancreas recipients. Higher Amylase1, Liplase1, Amylasemax, and Lipasemax were associated with an increase in early complications, mainly need for pancreatectomy, fluid collections, bleeding complications, or graft thrombosis, particularly in the solitary pancreas group. CONCLUSIONS: Our finding suggests that cases of early perioperative enzyme increase merit consideration for early imaging investigation to mitigate detrimental outcomes.

Association of human leukocyte antigen mismatches between donor-recipient and donor-donor in pancreas after kidney transplant recipients.

The effects of HLA mismatching on pancreas outcomes among pancreas after kidney (PAK) recipients are undefined. Outcomes might potentially differ depending on whether there is a mismatch between pancreas donor and recipient (PD-R) or pancreas donor and kidney donor(PD-KD). All primary PAK at our centre were included in this study. Patients were divided into two groups based on the degree of HLA mismatching: low (L-MM) as 0-4 and high (H-MM) as 5-6. We analysed all (N = 73) PAK for PD-R mismatch and the subset of PAK for PD-KD mismatch (N = 71). Comparing PD-R L-MM (n = 39) and H-MM (n = 34) PAKs, we observed no difference in the rate of pancreas graft failure. There was also no difference in the rate of rejection (L-MM 33% vs. H-MM 41%) or the severity of rejection. However, we observed a significantly (P < 0.01) shorter time to acute pancreas rejection in the H-MM group (6.8 ± 8.7 mo) versus the L-MM cohort (29.0 ± 36.2 mo) (P < 0.001). Similar to the PD-R mismatched cohort, we did not observe a detrimental effect of HLA mismatching on graft outcomes in the PD-KD cohort; time to rejection was again shorter in the H-MM subset. In this study, we found no impact of HLA mismatch on either pancreas graft survival or rejection rates, though rejection occurred earlier in high mismatched PAK transplants.

Tomotherapy Applied Total Lymphoid Irradiation and Allogeneic Hematopoietic Cell Transplantation Generates Mixed Chimerism in the Rhesus Macaque Model.

Development of a new methodology to induce immunological chimerism after allogeneic hematopoietic cell (HC) transplantation in a rhesus macaque model is described. The chimeric state was achieved using a non-myeloablative, helical tomotherapy-based total lymphoid irradiation (TomoTLI) conditioning regimen followed by donor HC infusions between 1-haplotype matched donor/recipient pairs. The technique was tested as a feasibility study in an experimental group of seven rhesus macaques that received the novel TomoTLI tolerance protocol and HC allo-transplants. Two tomotherapy protocols were compared: TomoTLI (n = 5) and TomoTLI/total-body irradiation (TBI) (n = 2). Five of seven animals developed mixed chimerism. Three of five animals given the TomoTLI protocol generated transient mixed chimerism with no graft-versus-host disease (GVHD) with survival of 33, 152 and >180 days. However, the inclusion of belatacept in addition to a single fraction of TBI resulted in total chimerism and fatal GVHD in both animals, indicating an unacceptable conditioning regimen.

Belatacept for Simultaneous Calcineurin Inhibitor and Chronic Corticosteroid Immunosuppression Avoidance: Two-Year Results of a Prospective, Randomized Multicenter Trial.

BACKGROUND AND OBJECTIVES: Immunosuppressive therapy in kidney transplantation is associated with numerous toxicities. CD28-mediated T-cell costimulation blockade using belatacept may reduce long-term nephrotoxicity, compared with calcineurin inhibitor-based immunosuppression. The efficacy and safety of simultaneous calcineurin inhibitor avoidance and rapid steroid withdrawal were tested in a randomized, prospective, multicenter study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study reports the 2-year results of a randomized clinical trial of 316 recipients of a new kidney transplant. All kidney transplants were performed using rapid steroid withdrawal immunosuppression. Recipients were randomized in a 1:1:1 ratio to receive belatacept with alemtuzumab induction, belatacept with rabbit anti-thymocyte globulin (rATG) induction, or tacrolimus with rATG induction. The composite end point consisted of death, kidney allograft loss, or an eGFR of <45 ml/min per 1.73 m2 at 2 years. RESULTS: The composite end point was observed for 11 of 107 (10%) participants assigned to belatacept/alemtuzumab, 13 of 104 (13%) participants assigned to belatacept/rATG, and 21 of 105 (21%) participants assigned to tacrolimus/rATG (for belatacept/alemtuzumab versus tacrolimus/rATG, P=0.99; for belatacept/rATG versus tacrolimus/rATG, P=0.66). Patient and graft survival rates were similar between all groups. An eGFR of <45 ml/min per 1.73 m2 was observed for nine of 107 (8%) participants assigned to belatacept/alemtuzuab, eight of 104 (8%) participants assigned to belatacept/rATG, and 20 of 105 (19%) participants assigned to tacrolimus/rATG (P<0.05 for each belatacept group versus tacrolimus/rATG). Biopsy sample-proven acute rejection was observed for 20 of 107 (19%) participants assigned to belatacept/alemtuzuab, 26 of 104 (25%) participants assigned to belatacept/rATG, and seven of 105 (7%) participants assigned to tacrolimus/rATG (for belatacept/alemtuzumab versus tacrolimus/rATG, P=0.006; for belatacept/rATG versus tacrolimus/rATG, P<0.001). Gastrointestinal and neurologic adverse events were less frequent with belatacept versus calcineurin-based immunosuppression. CONCLUSIONS: Overall 2-year outcomes were similar when comparing maintenance immunosuppression using belatacept versus tacrolimus, and each protocol involved rapid steroid withdrawal. The incidence of an eGFR of <45 ml/min per 1.73 m2 was significantly lower with belatacept compared with tacrolimus, but the incidence of biopsy sample-proven acute rejection significantly higher. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Belatacept Early Steroid Withdrawal Trial, NCT01729494.

Altered serum levels of autophagy proteins Beclin-1 and mTOR in patients with exudative age-related macular degeneration.

Autophagy is a key process in the maintenance of cellular survival and homeostasis. Inhibition of autophagy results in degenerative changes resembling ageing. We wondered if autophagy can contribute to the pathogenesis of age-related macular degeneration (AMD). We aimed to investigate the serum concentrations of two key autophagy regulators, Beclin-1 and mechanistic target of rapamycin (mTOR), in patients with exudative AMD. This retrospective case-control study included 38 patients with exudative AMD and 36 sex- and age-matched controls selected among senile cataract patients. Circulating Beclin-1 and mTOR were assessed using an enzyme-linked immunosorbent assay. The proteins levels were correlated with age, sex, duration of ocular symptoms, as well as angiographic and optical coherence tomography findings. Serum Beclin-1 levels were much lower in patients with AMD than in controls (median, 0.100 ng/ml versus 1.123 ng/ml; p = 0.0033), while mTOR levels did not differ (median, 4.377 ng/ml versus 3.608 ng/ml; p = 0.4522). Participants of the study older than 70 years had lower Beclin-1 levels than younger ones (p = 0.0444). However, this difference was the most evident in patients with AMD (p = 0.0024). Serum mTOR levels increased with age. In patients with AMD, lower mTOR levels were associated with drusen, while higher levels were observed in those with a fibrous scar in the contralateral eye (p = 0.0212). Our findings suggest that circulating Beclin-1 decreases with age and that is downregulated in patients with AMD.

Complex Ureteral Reconstruction in Kidney Transplantation.

OBJECTIVES: Despite advances in surgical techniques and organ preservation, transplant ureteric strictures remain a common complication in kidney transplantation. A variety of endourological and surgical techniques have been utilized; however, there is a lack of consensus on the optimal modality in dealing with these complex cases. MATERIALS AND METHODS: We present challenging ureteral reconstruction cases after failed attempts at ureteral dilatation, failed conventional open repairs, and/or with bladder dysfunction. RESULTS: All renal allografts were salvaged by successful use of bladder Boari flap and intestinal segment interpositions/diversions. CONCLUSIONS: Operative repair remains the most durable and successful approach, and minimally invasive options should be reserved for nonsurgical candidates, with consideration of a single attempt in patients with early, distal, short (<2 cm), nonischemic strictures.

Association of clinical factors and recent anticancer therapy with COVID-19 severity among patients with cancer: a report from the COVID-19 and Cancer Consortium.

BACKGROUND: Patients with cancer may be at high risk of adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We analyzed a cohort of patients with cancer and coronavirus 2019 (COVID-19) reported to the COVID-19 and Cancer Consortium (CCC19) to identify prognostic clinical factors, including laboratory measurements and anticancer therapies. PATIENTS AND METHODS: Patients with active or historical cancer and a laboratory-confirmed SARS-CoV-2 diagnosis recorded between 17 March and 18 November 2020 were included. The primary outcome was COVID-19 severity measured on an ordinal scale (uncomplicated, hospitalized, admitted to intensive care unit, mechanically ventilated, died within 30 days). Multivariable regression models included demographics, cancer status, anticancer therapy and timing, COVID-19-directed therapies, and laboratory measurements (among hospitalized patients). RESULTS: A total of 4966 patients were included (median age 66 years, 51% female, 50% non-Hispanic white); 2872 (58%) were hospitalized and 695 (14%) died; 61% had cancer that was present, diagnosed, or treated within the year prior to COVID-19 diagnosis. Older age, male sex, obesity, cardiovascular and pulmonary comorbidities, renal disease, diabetes mellitus, non-Hispanic black race, Hispanic ethnicity, worse Eastern Cooperative Oncology Group performance status, recent cytotoxic chemotherapy, and hematologic malignancy were associated with higher COVID-19 severity. Among hospitalized patients, low or high absolute lymphocyte count; high absolute neutrophil count; low platelet count; abnormal creatinine; troponin; lactate dehydrogenase; and C-reactive protein were associated with higher COVID-19 severity. Patients diagnosed early in the COVID-19 pandemic (January-April 2020) had worse outcomes than those diagnosed later. Specific anticancer therapies (e.g. R-CHOP, platinum combined with etoposide, and DNA methyltransferase inhibitors) were associated with high 30-day all-cause mortality. CONCLUSIONS: Clinical factors (e.g. older age, hematological malignancy, recent chemotherapy) and laboratory measurements were associated with poor outcomes among patients with cancer and COVID-19. Although further studies are needed, caution may be required in utilizing particular anticancer therapies. CLINICAL TRIAL IDENTIFIER: NCT04354701.

The Fourth International Workshop on Clinical Transplant Tolerance.

The International Workshop on Clinical Transplant Tolerance is a biennial meeting that aims to provide an update on the progress of studies of immunosuppression minimization or withdrawal in solid organ transplantation. The Fourth International Workshop on Clinical Tolerance was held in Pittsburgh, Pennsylvania, September 5-6, 2019. This report is a summary of presentations on the status of clinical trials designed to minimize or withdraw immunosuppressive drugs in kidney, liver, and lung transplantation without subsequent evidence of rejection. All protocols had in common the use of donor or recipient cell therapy combined with organ transplantation. The workshop also included presentations of mechanistic studies designed to improve understanding of the cellular and molecular basis of tolerance and to identify potential predictors/biomarkers of tolerance. Strategies to enhance the safety of hematopoietic cell transplantation and to improve patient selection/risk stratification for clinical trials were also discussed.

Phase 3 trial of human islet-after-kidney transplantation in type 1 diabetes.

Allogeneic islet transplant offers a minimally invasive option for ß cell replacement in the treatment of type 1 diabetes (T1D). The CIT consortium trial of purified human pancreatic islets (PHPI) in patients with T1D after kidney transplant (CIT06), a National Institutes of Health-sponsored phase 3, prospective, open-label, single-arm pivotal trial of PHPI, was conducted in 24 patients with impaired awareness of hypoglycemia while receiving intensive insulin therapy. PHPI were manufactured using standardized processes. PHPI transplantation was effective with 62.5% of patients achieving the primary endpoint of freedom from severe hypoglycemic events and HbA1c  ≤ 6.5% or reduced by ≥ 1 percentage point at 1 year posttransplant. Median HbA1c declined from 8.1% before to 6.0% at 1 year and 6.3% at 2 and 3 years following transplant (P < .001 for all vs baseline), with related improvements in hypoglycemia awareness and glucose variability. The improved metabolic control was associated with better health-related and diabetes-related quality of life. The procedure was safe and kidney allograft function remained stable after 3 years. These results add to evidence establishing allogeneic islet transplant as a safe and effective treatment for patients with T1D and unstable glucose control despite intensive insulin treatment, supporting the indication for PHPI in the post-renal transplant setting.

Effect of photodynamic therapy with verteporfin on tumor thickness and best corrected visual acuity in patients with circumscribed choroidal hemangioma: a single-center experience.

The management of circumscribed choroidal hemangioma (CCH) with photodynamic therapy (PDT) using verteporfin has resulted in significant functional and clinical improvement compared with the pre-PDT era. Literature data on factors influencing clinical outcomes and predictors of response to PDT in symptomatic CCH are inconsistent. The aim of this study was to investigate the efficacy of PDT with verteporfin in patients with CCH depending on symptom duration and tumor thickness at baseline. We analyzed the medical records of 37 patients with symptomatic CCH divided into 3 groups according to symptom duration (≤ 50 weeks, 51 - 100 weeks, and > 100 weeks) and into 2 groups according to tumor thickness (≤ 2.3 mm and > 2.3 mm). Patients were subjected to PDT with verteporfin at a concentration of 6 mg/m2 body surface area and a light dose of 50 J/cm2 at a wavelength of 689 nm. The mean number of treatment sessions was 1.57 (range, 1 - 3). Tumor thickness, the transverse and longitudinal diameters of the tumor base, and best corrected visual acuity (BCVA) were evaluated at baseline and at 12 - 15 months after treatment. After PDT, the mean tumor thickness in the whole study group decreased by 1.19 ± 0.66 mm (from 3.14 mm to 1.95 mm). Subgroup analyses revealed no significant differences between the 2 groups divided according to tumor thickness (p = 0.49). However, tumor thickness differed significantly between the 3 groups divided according to symptom duration (p < 0.05). BCVA increased in 22 patients (59.5%), remained unchanged in 12 patients (16.2%), and decreased in 3 patients (10.1%). Our study provides evidence for the efficacy of PDT with verteporfin in terms of improving or stabilizing visual function as well as reducing tumor thickness in patients with CCH, including those with long-lasting disease.

The demise of islet allotransplantation in the United States: A call for an urgent regulatory update.

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.

Central serous chorioretinopathy induced by drugs metabolized by cytochrome P450 3A4.

The purpose of this study was investigate whether replacing or discontinuing drugs that are inhibitors or substrates of cytochrome P450 3A4 (CYP3A4) may improve the clinical course of central serous chorioretinopathy (CSC). A retrospective observational study included 43 patients with active CSC. Twenty seven patients (32 eyes, group 1) were using drugs that act as substrates or inhibitors of CYP3A4. In 25 of these 27 patients, treatments including steroids, calcium channel blockers, anticoagulants, statins, beta-adrenolytics, angiotensin receptor antagonists, antidepressants, muscarinic receptor antagonists, phosphodiesterase type 5 inhibitors, and others were discontinued or replaced with medications not affecting CYP3A4. Sixteen patients (19 eyes, group 2) not using any medication that affects CYP3A4, were given eplerenone, rifampicin, or laser treatment. Main outcomes measures were assessed by functional and anatomical images obtained using multimodal imaging techniques. The average follow-up time was 12 months. In group I after discontinuing or replacing substrates or inhibitors of CYP3A4, improvements were observed in 18 patients (22 eyes). None of the patients that were using drugs affecting CYP3A4 improved with eplerenone therapy, however, all 18 patients improved after discontinuing the drugs. All these drugs had a blocking effect on eplerenone therapy. Best corrected visual acuity (BCVA) improved in 14 eyes, remained unchanged in 5 eyes, and worsened in 3 eyes. In 21 of the 22 eyes, subretinal fluid absorption was observed with optical coherence tomography (OCT). Mean central retinal thickness decreased from 361 µm to 219 µm. One patient (2 eyes) was unable to change treatment (due to neoplasm), one patient (1 eye) did not agree to change or stop treatment, and seven patients (7 eyes) were lost to follow-up. Of the 16 patients (19 eyes) who were treated with eplerenone, rifampicin, or laser, improvements were observed in 14 patients (16 eyes), two patients (2 eyes) were lost to follow-up, and CSC worsened in 1 eye. We concluded that patients with CSC should not take substrates or inhibitors of CYP3A4. These drugs should be replaced with alternatives that act through other metabolic pathways.