Effect of Modified Vertical Rectus Belly Transposition vs Augmented Superior Rectus Transposition Plus Medial Rectus Recession for Chronic Sixth Nerve Palsy: A Randomized Clinical Trial.

Importance: Both vertical rectus belly transposition (VRBT) and superior rectus transposition (SRT) can be performed simultaneously with ipsilateral medial rectus recession (MRc) and have been shown to be effective for chronic sixth nerve palsy. However, it is unclear whether VRBT is superior to SRT in correcting esotropia. Objective: To compare the effectiveness of modified VRBT plus MRc (mVRBT-MRc) vs augmented SRT plus MRc (aSRT-MRc) in Chinese patients with chronic sixth nerve palsy. Design, Setting, and Participants: This parallel-design, double-masked, single-center, randomized clinical trial was conducted from January 15, 2018, to May 24, 2021. The follow-up visits were scheduled at 1 month and 6 months. Eligible Chinese participants with unilateral chronic sixth nerve palsy were randomly assigned to receive either mVRBT-MRc (VRBT group) or aSRT-MRc (SRT group). Interventions: mVRBT-MRc or aSRT-MRc. Main Outcomes and Measures: Change of horizontal deviation in primary position from baseline to 6 months. Results: Of the total 25 eligible participants, the mean (SD) age was 45.4 (12.6) years, with 10 male participants (40%) and 15 female participants (60%). Thirteen participants (52%) were randomly assigned to the VRBT group, and 12 (48%) were randomly assigned to the SRT group. At baseline, the mean (SD) horizontal deviation was 65.7 (10.8) prism diopters (Δ) in the VRBT group and 60.5Δ(14.1Δ) in the SRT group. Similar amounts of MRc were performed in both groups. At 6 months, the horizontal deviation changed from baseline by 66.3Δ in the VRBT group and by 51.5Δ in the SRT group. The adjusted group difference was 10.9Δ (95% CI, 5.3Δ-16.6Δ), favoring the VRBT group (P = .001). Four times as many participants corrected more than 60Δ with mVRBT-MRc compared with aSRT-MRc. The group difference of the improvement of abduction limitation was -0.2 (95% CI, -0.8 to 0.5; P = .64). Although there was a higher proportion of undercorrection in the SRT group (difference, 45%; 95% CI, 16%-75%; P = .01), no differences were identified for other suboptimal outcomes between groups. Conclusions and Relevance: Compared with aSRT-MRc, mVRBT-MRc showed better effect in correcting esotropia with no differences detected for other suboptimal outcomes. mVRBT-MRc may be a promising alternative surgical procedure for chronic sixth nerve palsy, particularly for large esotropia of more than 60Δ, if these results are confirmed in larger, diverse cohorts with longer follow-up. Trial Registration: ChiCTR Identifier: ChiCTR-INR-17013705.

Diverting Enterostomy Improves Overall Survival of Patients With Severe Steroid-refractory Gastrointestinal Acute Graft-Versus-Host Disease.

OBJECTIVE: The aim of this study was to evaluate the benefit of diverting enterostomy (DE) in patients with severe steroid-refractory (SR) gastrointestinal acute graft-versus-host-disease (GI-aGVHD) following allogeneic hematopoietic stem-cell transplantation (ASCT). SUMMARY AND BACKGROUND DATA: Severe GI-aGVHD refractory to the first-line steroid therapy is a rare but dramatic life-threatening complication. Second lines of immunosuppressors have limited effects and increase the risk of sepsis. Data suggest that limiting GI bacterial translocation by DE could restrain severe GI-aGVHD. METHODS: From 2004 to 2018, we retrospectively reviewed all consecutive patients undergoing ASCT for hematologic malignancies who developed severe SR GI-aGVHD. We compared patients in whom a proximal DE was performed (Enterostomy group) with those not subjected to DE (Medical group). The primary endpoint was the 1-year overall survival (OS) measured from the onset of GI-aGVHD. Secondary endpoints were the 2-year OS and causes of death. RESULTS: Of the 1295 patients who underwent ASCT, 51 patients with severe SR GI-aGVHD were analyzed (13 in Enterostomy group and 38 in Medical group). Characteristics of patients, transplantation modalities, and aGVHD severity were similar in both groups. The 1-year OS was better after DE (54% vs 5%, P = 0.0004). The 2-year OS was also better in "Enterostomy group" (31% vs 2.5%; P = 0.0015), with a trend to lower death by sepsis (30.8% vs 57.9%; P = 0.091). CONCLUSION: DE should be considered for severe GI-aGVHD as soon as resistance to the corticosteroid is identified.

Ileostomy for steroid-resistant acute graft-versus-host disease of the gastrointestinal tract.

Steroid-resistant acute graft-versus-host disease (GVHD) of the gastrointestinal tract associates with important morbidity and mortality. While high-dose steroids are the established first-line therapy in GVHD, no second-line therapy is generally accepted. In this analysis of 65 consecutive patients with severe, steroid-resistant, intestinal GVHD (92% stage 4), additional ileostomy surgery significantly reduced overall mortality (hazard ratio 0.54; 95% confidence interval, 0.36-0.81; p = 0.003) compared to conventional GVHD therapy. Median overall survival was 16 months in the ileostomy cohort compared to 4 months in the conventional therapy cohort. In the ileostomy cohort, both infectious- and GVHD-associated mortality were reduced (40% versus 77%). Significantly declined fecal volumes (p = 0.001) after surgery provide evidence of intestinal adaptation following ileostomy. Correlative studies indicated ileostomy-induced immune-modulation with a > 50% decrease of activated T cells (p = 0.04) and an increase in regulatory T cells. The observed alterations of the patients' gut microbiota may also contribute to ileostomy's therapeutic effect. These data show that ileostomy induced significant clinical responses in patients with steroid-resistant GVHD along with a reduction of pro-inflammatory immune cells and changes of the intestinal microbiota. Ileostomy is a treatment option for steroid-resistant acute GVHD of the gastrointestinal tract that needs further validation in a prospective clinical trial.

Favorable Outcome of Lung Transplantation for Severe Pulmonary Graft Versus Host Disease: An Australian Multicenter Case Series.

BACKGROUND: Severe pulmonary chronic graft versus host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation. Few treatments influence outcome, with 5-year overall survival as low as 13%. Lung transplantation (LTx) has been reported in small numbers of patients worldwide. METHODS: We investigated the outcomes of LTx performed for this indication at 2 large Australian LTx centers. RESULTS: Eighteen patients (aged 10-64 y; median, 29.6 y) received bilateral deceased lung transplants for pulmonary chronic GVHD between 2002 and 2017. LTx was performed at a median of 8.6 years after allogeneic stem cell transplantation (range, 2-23 y) with a median interval of 16 months from the time of transplant unit review to LTx. There were 2 early infective deaths and 3 further deaths from pulmonary infection and lung allograft rejection. There were no primary disease relapses. At a median follow-up of 5 years, the 5-year overall survival post-LTx is 80% and comparable to the Australia and New Zealand registry data of 64% for LTx performed for all indications. CONCLUSIONS: From one of the largest series of deceased LTx for this indication, we conclude that it is a feasible option for selected patients with severe pulmonary GVHD. The outcomes appear superior to that of non-LTx-based therapies and similar to the survival of the general LTx population. Establishing guidance on referral triggers, patient eligibility, organ selection, prophylaxis of allograft rejection, and supportive care would assist hematopoietic and lung transplant units in optimizing resource allocation and patient outcomes.

Allogeneic donor split skin grafts for treatment of refractory ulcers in cutaneous chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation-a retrospective analysis on seven patients.

Refractory skin ulcers due to severe chronic graft-versus-host disease (cGVHD) remain to be associated with significant morbidity and mortality.We performed an allogeneic donor skin transplantation in seven adult patients after allogeneic hematopoietic stem cell transplantation for cGVHD-associated refractory skin ulcers. While four patients received a split skin graft (SSG), in one patient, a full thickness skin graft for two small refractory ulcers of the ankle was performed, and one patient received in vitro expanded donor keratinocyte grafts derived from hair roots of the original unrelated donor. In one additional patient, a large deep fascial defect of the lower leg was covered with an autologous greater omentum free graft before coverage with an allogeneic SSG. An additional patient was treated with an autologous scrotal skin graft for a refractory ulcer associated with deep sclerosis of cGVHD after unrelated donor transplantation.All skin grafts engrafted and resulted in permanent coverage of the grafted ulcers without any signs of immunological mediated damage. In the patient receiving in vitro expanded keratinocyte grafts, two localized ulcers were permanently covered by donor skin while this approach failed to cover extensive circular ulcers of the lower legs.Allogeneic donor skin grafts are a valuable treatment option in refractory ulcers due to cGVHD but are restricted mainly to related donors while keratinocyte grafts from unrelated donors remain experimental. In male patients lacking a related donor, autologous scrotal skin graft may be an alternative option.

Clinical and Dermoscopic Evaluation of Melanocytic Lesions in Patients with Chronic Graft Versus Host Disease.

Patients treated with haematopoietic stem cell transplantation are at increased risk of cutaneous malignant neoplasms. There are no reports on the characteristics of melanocytic lesions in patients with chronic graft versus host disease and the value of recognizing these difficult lesions in high-risk patients. The objective of this study is to describe the clinical and dermoscopic characteristics of melanocytic lesions in patients with chronic graft versus host disease in order to understand their morphology. A prospective cross-sectional study was performed; 10 melanocytic lesions on the trunk and extremities were selected from each patient. A statistically significant association was found between regression and high total dermoscopic score and 7-point checklist score. Lesions were excised or included in short-term digital follow-up. Melanocytic lesions in patients with chronic graft versus host disease developing after allogeneic-haematopoietic stem cell transplantation exhibit marked structural and colour changes similar to melanoma. This is believed to result from the inflammatory process associated with graft versus host disease.

Subconjunctival injection of mesenchymal stromal cells protects the cornea in an experimental model of GVHD.

PURPOSE: To evaluate the therapeutic effect of subconjunctival injection of human mesenchymal stromal cells (hMSCs) in the cornea of mice with graft versus host disease (GVHD). METHODS: GVHD was induced in mice after hematopoietic stem cell transplantation (HSCT) between MHC-mismatched mouse strains. Subconjunctival injection of hMSCs was applied at day 10 post-HSCT. Infiltration of CD3+ cells in the cornea and epithelial alterations were analyzed by immunofluorescence. Tear was assessed using the PRT test and TearLab Osmolarity System. qPCR was used to evaluate changes in cytokines, Pax6 and Sprr1b expression. To evaluate the effect of irradiation, we analyzed the expression of these genes in TBI mice. RESULTS: Immune cell invasion occurs in mice with GVHD, as shown by the presence of CD3+ cells in the cornea. Interestingly, eyes treated with hMSC did not present CD3+ cells. Tear osmolarity was increased in GVHD eyes, but not in treated eyes. TNFa expression was highly increased in all corneas except in Control and treated eyes. Pax6 in corneal epithelium showed a similar pattern in GVHD and Control mice, and its gene expression was enhanced in GVHD corneas. In contrast, Pax6 was reduced in GVHD + MSC corneas. We also found an increase in SPRR1B staining in GVHD eyes that was lower in GVHD + MSC mice, demonstrating that corneal keratinization is less frequent after treatment with hMSC. CONCLUSIONS: The treatment with hMSCs by subconjunctival injection is effective in reducing corneal inflammation and squamous metaplasia in ocular GVHD (oGVHD). Local treatment with hMSCs is a promising strategy for oGVHD.

Long-Term Follow-Up of Sexual Dysfunction in Women Following Allogeneic Hematopoietic Stem Cell Transplantation.

Chronic graft-versus-host disease is the most common late complication following allogeneic hematopoietic stem cell transplantation. The aim of this study was to present the outcomes of two successful vaginal reconstructions. Patient 1 received chemotherapy for leukemia and underwent bone marrow transplantation (BMT). The patient was sexually inactive for 9 years. In 2012, she was diagnosed with complete vaginal obliteration and underwent vaginal reconstruction. Patient 2 underwent chemotherapy (myeloablative therapy), was sexually inactive for 3 years and was then diagnosed with complete vaginal obliteration. In January 2013, she had vaginal reconstruction with cervical dilatation. Hormonal replacement therapy was administered to both patients. The results of dedicated questionnaires revealed decent quality-of-life and normal sexual functioning and continence status after surgery. Obliteration of the vagina after BMT can be prevented, but if it occurs, vaginal reconstruction surgery should be offered to any patients suffering from obliteration. Our results show that this therapy enables patients to have normal sexual lives without compromising their continence status.

Solid organ transplantation after hematopoietic stem cell transplantation in childhood: A multicentric retrospective survey.

We report data obtained from a retrospective multicenter pediatric survey on behalf of the European Society for Blood and Marrow Transplantation (EBMT). Information on solid organ transplantation (SOT) performed in pediatric recipients of either autologous or allogeneic hematopoietic stem cell transplantation (HSCT) between 1984 and 2016 was collected in 20 pediatric EBMT Centers (25.6%). Overall, we evaluated data on 44 SOTs following HSCT including 20 liver (LTx), 12 lung (LuTx), 6 heart (HTx), and 6 kidney (KTx) transplantations. The indication for SOT was organ failure related to intractable graft-vs-host disease in 16 children (36.3%), acute or chronic HSCT-related toxicity in 18 (40.9%), and organ dysfunction related to the underlying disease in 10 (22.8%). The median follow-up was 10.9 years (95% confidence interval: 1.7-29.5). The overall survival rate at 1 and 5 years after SOT was 85.7% and 80.4%, respectively: it was 74% and 63.2% after LTx, 83.2% after HTx, and 100% equally after LuTx and KTx. This multicenter survey confirms that SOT represents a promising option in children with severe organ failure occurring after HSCT. Additional studies are needed to further establish the effectiveness of SOT after HSCT and to better understand the mechanism underlying this encouraging success.

Tratamiento con células mesenquimales de la enfermedad de injerto contra huésped como complicación de trasplante hepático / Treatment of graft-versus-host disease with mesenchymal cells as a complication of a liver transplantation

Presentamos el caso de un paciente trasplantado hepático (TH) de donante cadáver que desarrolló una enfermedad de injerto contra huésped (EICH) agudo, cuyas manifestaciones fundamentales fueron rash cutáneo, diarrea y pancitopenia. Como parte del tratamiento se administraron células mesenquimales. Hasta la fecha no se han descrito en la literatura casos de EICH post-TH tratados con células mesenquimales. A pesar del tratamiento, no se produjo mejoría en la aplasia ni en la clínica gastrointestinal y el paciente falleció por una infección diseminada

We present the case of a liver transplant (LT) recipient donor who developed graft versus host disease (GVHD). The main features were cutaneous rash, diarrhea and pancytopenia. Mesenchymal cells were administered as part of the treatment. This is the first case of a patient with GVHD after LT reported to date. Despite the treatment, there was no improvement in aplasia or gastrointestinal symptoms and the patient died due to a disseminated infection

Treatment of graft-versus-host disease with mesenchymal cells as a complication of a liver transplantation.

We present the case of a liver transplant (LT) recipient donor who developed graft versus host disease (GVHD). The main features were cutaneous rash, diarrhea and pancytopenia. Mesenchymal cells were administered as part of the treatment. This is the first case of a patient with GVHD after LT reported to date. Despite the treatment, there was no improvement in aplasia or gastrointestinal symptoms and the patient died due to a disseminated infection.

Translation of Clinical Research into Practice: An Impact Assessment of the Results from the Blood and Marrow Transplant Clinical Trials Network Protocol 0201 on Unrelated Graft Source Utilization.

Barriers and facilitators to adoption of results of clinical trials are substantial and poorly understood. We sought to examine whether the results of the randomized, multicenter Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0201 study comparing peripheral blood (PB) with bone marrow (BM) stem cells for unrelated donor (URD) hematopoietic cell transplantation (HCT) changed practice from PB to BM graft utilization and explored factors that impact graft selection and translation of research results into practice. The difference between use of URD BM and PB in the 2 years before and after publication of results in 2012 was examined using observational data collected by the Center for Blood and Marrow Transplant Research. A web-based survey of transplant physicians was conducted to understand the change in physician-reported personal and center preferred URD graft. No significant change in use of BM versus PB grafts occurred after 2012. Both BMT CTN participating and nonparticipating centers continued to use PB. Ninety-two percent of respondents were aware of the study results; 18% reported a change in personal and 16% reported a change in their center's practice of requesting BM instead of PB for URD HCT. Patient characteristics and the perception that engaging local champions to increase the evidence uptake were factors associated with personal or center change in practice. Despite awareness of the trial results, fewer than one-fifth of HCT physicians reported practice change in response to the BMT CTN 0201 results. Observational data confirmed no discernible change in practice.

Small bowel stenosis: a manifestation of chronic graft-versus-host disease in children?

Digestive graft-versus-host disease (GVHD) is a frequent complication after bone marrow transplantation, but small bowel obstruction is an extremely rare event. We present herein the first pediatric series of 4 cases of small bowel obstruction after bone marrow transplantation with detailed gross, histological data and their genetic status of the NOD2 gene. All patients had a history of severe acute GVHD treated by immunosuppressive agents and/or infliximab (in 3 cases). Acute or progressively worsening abdominal pain accompanied by small bowel occlusion occurred 5-16 months after graft, and computed tomographic scan revealed multiple small intestinal stenoses. Failure of intensive medical treatment led to surgical resection of affected loops. Stigmata of acute (apoptosis of crypts and satellitosis) and chronic GVHD features (submucosal fibrosis and serosae sclerolipomatosis), as well as extensive ulcerations, were observed in all ileal specimens. NOD2 mutation was found in only 1 patient. The follow-up showed successful outcome after surgery.

The association between acute graft-versus-host disease and antimicrobial peptide expression in the gastrointestinal tract after allogeneic stem cell transplantation.

Intestinal microbiota disruption is associated with acute gastrointestinal (GI) Graft-versus-Host Disease (GvHD) and poor outcome after allogeneic stem cell transplantation (ASCT). Here, in a retrospective analysis of 200 patients undergoing ASCT at the Regensburg University Medical Center, we assessed the relative expression of Paneth cell antimicrobial peptides (AMPs), Human Defensins (HD) 5 and 6 and regenerating islet-derived 3α (Reg3α), in 292 human intestinal biopsies as well as Reg3α serum levels in relation to acute GI GvHD. In the absence of GI GvHD, the relative expression of Paneth cell AMPs was significantly higher in the small intestine (duodenum to ileum) than in the stomach and large intestine (cecum to rectum) for Reg3α (p≤0.001), HD5 (p≤0.002) and HD6 (p≤0.02). Acute stage 2-4 GI GvHD was associated with reduced expression of AMPs in the small intestine (p≤0.01) in comparison to stage 0-1 disease, accompanied by a decrease in Paneth cell count in case of severe acute GI GvHD (p<0.001). The opposite held true for the large intestine as we found stage 2-4 GI GvHD correlated with significantly higher expression of HD5, HD6, and Reg3α compared to mild or no acute GI GvHD (p≤0.002). Severe GI GvHD in both the lower and the upper GI tract also correlated with higher serum concentrations of Reg3α (p = 0.002). As indirect markers of intestinal microbiome diversity low levels of urinary 3-indoxyl sulfate levels were associated with severe stages of acute GI GvHD compared to mild stage or no acute GI GvHD (p = 0.05). In conclusion, acute GI GvHD correlates with intestinal expression of HD5, HD6 and Reg3α as well as Reg3α serum levels and is associated with intestinal dysbiosis.

Graft versus host disease: what should the oculoplastic surgeon know?

PURPOSE OF REVIEW: To provide a concise review of the oculoplastic manifestations of ocular graft versus host disease (GVHD), and to discuss their management. RECENT FINDINGS: Ocular GVHD occurs as a common immune-mediated complication of hematopoietic stem cell transplantation that presents as a Stevens-Johnson-like syndrome in the acute phase or a Sjögren-like syndrome in the chronic phase. Cicatricial conjunctivitis may be underreported in ocular GVHD. The spectrum of oculoplastic manifestations includes GVHD of the skin, cicatricial entropion, nasolacrimal duct obstruction, and lacrimal gland dysfunction. Surgical treatment is indicated for patients with significant corneal complications from entropion. Surgical approach to repair of nasolacrimal duct obstruction is presented in this review, including modified approaches for treating patients at risk for keratitis sicca. Management of the ocular graft versus host patient may require a multidisciplinary approach involving collaboration from the oculoplastic surgeon, the corneal specialist, and the stem cell transplant physician. SUMMARY: Oculoplastic manifestations of ocular GVHD typically present as cicatricial changes in the eyelid and lacrimal system. Careful oculoplastic and corneal evaluation are necessary when considering surgical management for the ocular GVHD patient.

Successful Single-Lung Transplant for Severe Lung Graft-Versus-Host Disease Two Years After Sibling Allograft for Acute Lymphoblastic Leukemia: A Case Report.

Bone marrow transplantation (BMT) has been performed as a successful life-saving treatment for hematological and neoplastic diseases. Despite the predictable long-term survival rates in BMT, pulmonary complications reduce the survival rates significantly mainly because of chronic graft-versus-host disease (GVHD). This report briefly discusses a successful lung transplantation case for severe lung GVHD after allograft for acute lymphoblastic leukemia. This case report supports the scarce evidence in the literature for the importance of lung transplantation as a therapeutic option for patients who develop respiratory failure secondary to BMT.

Successful T-cell Replete Hematopoietic Stem Cell Boost Without Conditioning for Late Graft Failure.

Late graft failure is a rare but significant complication after allogeneic stem cell transplantation, which is often complicated by severe infections. We report a case of late graft failure, which was successfully treated with a T-cell replete hematopoietic stem cell boost without conditioning that induced rapid engraftment and relieved the patient of infection. Discontinuation of immunosuppressants and nilotinib administration suppressed the host cells. Achieving full donor chimerism allowed us to administer a peripheral blood stem cell boost without conditioning.