Updates in chronic graft-versus-host disease

Chronic graft-versus-host disease (GVHD) is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. Symptoms and manifestations of chronic GVHD are heterogeneous and pleomorphic, and there are no standard treatments beyond corticosteroids. Therapy is typically prolonged, and chronic GVHD and its treatment are associated with adverse effects that have a significant impact on long-term quality of life and functional status. Several advances have been made over the last 2 decades to define the diagnosis of chronic GVHD as well as its severity and response criteria for clinical trials. Further understanding into the biologic mechanisms of the development of chronic GVHD has led to the investigation of several novel immunomodulatory and targeted therapies. Multi-institutional collaboration and pharmaceutical support in the development of therapies based on sound biologic mechanisms and clinical trials with defined end points and responses have led to several promising agents on the horizon of approval for treatment of chronic GVHD. This article reviews advances in our knowledge of chronic GVHD and its biologic framework to improve approaches to prevention and treatment.

O-BN02 Laparoscopic subtotal cholecystectomy for difficult gallbladders: A lifesaving bailout or an incomplete operation? A systematic review

Background Cholecystectomy is one of the commonest abdominal operations performed worldwide. Sometimes, the operation can be technically difficult due to dense adhesions in Calot’s triangle. Conversion to open surgery or subtotal cholecystectomy have been described to deal with these situations. A recent systematic review and meta-analysis on STC suggested high perioperative morbidity associated with STC. These findings are at odds with a previous systematic review and meta-analysis on the topic which concluded that morbidity rates for STC were comparable to those reported for total cholecystectomy. However, both these reviews included patients undergoing Open Subtotal Cholecystectomy (OSTC). This makes it difficult for us to understand the outcomes of LSTC as surgeons are not faced with the choice of converting to open surgery to perform a subtotal cholecystectomy. The choice they face is whether they should perform a LSTC or convert to open surgery to perform a total cholecystectomy. It is, therefore, important to establish the outcomes of LSTC alone (without including patients who underwent OSTC). This is all the more important during COVID-19 pandemic when the complexity of gall stone disease appears to have worsened. There is thus an enhanced need to understand technical nuances and outcomes of LSTC alone. Methods Search strategy: We searched PUBMED (Medline), Google Scholar, and Embase for all relevant English language articles describing experience with LSTC in adult human population (≥18 years) anywhere in the world using key-words like “subtotal cholecystectomy”, “gallbladder resection”, “gallbladder excision”, “gallbladder removal”, “partial”, “incomplete”, “insufficient”, “deroofing”, and “near-total”. Case reports, articles only published as conference abstracts, case series with <5 cases, and reviews were excluded. Only English-language studies were included. Participants: All studies with 5 or more cases, describing any experience with an adult cohort (≥18 years) of patients undergoing STC while attempting a Laparoscopic Cholecystectomy were included. Studies on patients who underwent preoperative cholecystostomy were excluded. Studies that had LSTC as part of another surgery were also excluded as we wanted to understand the morbidity and mortality of LSTC alone. Studies on patients who underwent OSTC (Open from start) were excluded as were those where the LSTC cohort was merged with the OSTC cohort and outcomes of LSTC were not separately reported. Study outcome: Primary outcome measure was early (≤30 days) morbidity and mortality. Secondary outcome measures were bile duct injury, bile leak rates, conversion to open surgery rates, duration of hospital stay, and late (>30 days) morbidity. Results 45 studies were identified, with a total of 2166 patients. Mean age was 55 +/- 15 years with 51% females; 53% (n = 390) were elective procedures. The conversion rate was 6.2% (n = 135). Most common indication was acute cholecystitis (n = 763). Different techniques were used with the majority having a closed cystic duct/gallbladder stump (n = 1188, 71%). The most common closure technique was intracorporeal suturing (53%) followed by endoloop closure. There were a total of four, 30-day mortality [1] in this review. Early morbidity (≤30 days) included bile duct injury (0.23%), bile leak rates (18%), intra-abdominal collection (4%). Reoperation was reported in 23 patients (1%), most commonly for unresolving intra-abdominal collections and failed ERCP to control bile leak. Long term follow-up was reported in 30 studies with a median follow up period of 22 months. Late morbidity included incisional hernias (6%), CBD stones (2%), and symptomatic gallstones in 4% (n = 41) with 2% (n = 22) requiring completion of cholecystectomy. Conclusions Laparoscopic subtotal cholecystectomy is an acceptable alternative in patients with a “difficult” Calot’s triangle. However, this has to be taken seriously as it is associated with a high early and late morbidity and mortality.

Non-relapse mortality among patients diagnosed with chronic GVHD: An updated analysis from The Chronic GVHD Consortium

Chronic graft-versus-host disease (GVHD) is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. To better understand patients at highest risk for non-relapse mortality (NRM), we analyzed patient, transplant, and chronic GVHD-related variables, risk factors, and causes of non-relapse deaths in an updated cohort of 937 subjects enrolled on two prospective, longitudinal observational studies through the Chronic GVHD Consortium. The median follow-up of survivors was 4 years (0.1 months - 12.5 years). Relapse accounted for 25% of the 333 deaths. The cumulative incidence of NRM was 22% at 5 years and increased over time with a projected 40% (95%CI, 30-50) at 12 years. Centers reported that chronic GVHD (37.8%) was the commonest cause of NRM and was associated with organ failure, infection, or additional cause not otherwise specified. The next most frequent causes without mention of chronic GVHD were infection (17%) and respiratory failure (10%). In multivariate analysis, an increased risk for NRM was significantly associated with the use of reduced intensity conditioning, higher total bilirubin, NIH skin score 2-3, NIH lung score 1-3, worse modified HAP adjusted activity score, and decreased distance on walk test. In conclusion, chronic GVHD NRM does not plateau but increases over time and is most commonly attributed to GVHD or infection, presumably associated with immunocompromised status. Severe skin and lung chronic GVHD remain challenging manifestations associated with increased NRM, for which novel therapeutic options are needed that do not predispose patients to infections.

HMP-S7 Is a Novel Anti-Leukemic Peptide Discovered from Human Milk

Chemotherapy in childhood leukemia is associated with late morbidity in leukemic survivors, while certain patient subsets are relatively resistant to standard chemotherapy. It is therefore important to identify new agents with sensitivity and selectivity towards leukemic cells, while having less systemic toxicity. Peptide-based therapeutics has gained a great deal of attention during the last few years. Here, we used an integrative workflow combining mass spectrometric peptide library construction, in silico anticancer peptide screening, and in vitro leukemic cell studies to discover a novel anti-leukemic peptide having 3+ charges and an alpha helical structure, namely HMP-S7, from human breast milk. HMP-S7 showed cytotoxic activity against four distinct leukemic cell lines in a dose-dependent manner but had no effect on solid malignancies or representative normal cells. HMP-S7 induced leukemic cell death by penetrating the plasma membrane to enter the cytoplasm and cause the leakage of lactate dehydrogenase, thus acting in a membranolytic manner. Importantly, HMP-S7 exhibited anti-leukemic effects against patient-derived leukemic cells ex vivo. In conclusion, HMP-S7 is a selective anti-leukemic peptide with promise, which requires further validation in preclinical and clinical studies.

Late morbidity and mortality among survivors of neuroblastoma treated with contemporary therapy: A report from the Childhood Cancer Survivor Study.

10044 Background: Survival rates for neuroblastoma vary widely based on risk group. Therapies have evolved over the past four decades to de-intensify treatment for individuals with low/intermediate risk disease and intensify therapy for those with high risk disease. Risk stratification is predicted to result in differential outcomes in late morbidity and mortality; the magnitude of these differences has not been well studied. Methods: We evaluated late mortality, subsequent malignant neoplasms (SMN) and chronic health conditions (CHC) graded according to CTCAE v4.03 among 491 5-year CCSS survivors of neuroblastoma diagnosed 1987-1999 at ≥1 year of age. Using age, stage at diagnosis, and treatment, survivors were classified into risk groups (low [n=182]; intermediate [n=70]; high [n=239]). Standardized mortality ratios (SMR) and standardized incidence ratios (SIR) of SMN were calculated using rates from NCHS and SEER, respectively. Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for CHC compared to 1,029 CCSS siblings. Results: Among survivors (48% male; median age 22 years, range 7-42; median follow-up 19 years, range 5-29), 80.4% with low risk disease were treated with surgery alone, while 77.8% with high risk disease received surgery, radiation, chemotherapy ± transplant. The 15-year cumulative incidence of all-cause mortality was 9.2% (CI: 7.1-11.4), with a recurrence-related mortality of 7.3% (CI: 5.3-9.3) and SMN-related mortality of 0.3% (CI: 0-0.7). All-cause mortality was significantly higher in all risk groups: (low, SMR=5.8 [CI: 2.6-13.0]; intermediate, SMR=5.7 [CI: 1.4-23.5]; high, SMR=38.6 [CI: 27.9-53.5]). The risk of SMN was elevated among high risk survivors (SIR=25.1, CI: 16.7-37.6), but did not differ from the US population for survivors of low or intermediate risk disease. Table describes the HR of CHCs (grades 1-5 and 3-5) in survivors, by risk group, as compared with siblings, as well as categories of CHCs for which survivors were at increased risk. Conclusions: Long-term survivors of neuroblastoma have a high risk of late morbidity and mortality; risk is particularly pronounced among survivors of high risk disease. Vigilant lifelong medical surveillance will be required for this relatively young population as they age.[Table: see text]

Pulmonary Vascular Resistance Measurement Remains Keystone in Congenital Heart Disease Management

Pulmonary vascular resistance (PVR) plays a major role in congenital heart management and critical decision. The impact of pulmonary vascular disease in the early and late morbidity and mortality after cardiac surgery and interventional catheterization in congenital heart defect (CHD) highlights the importance of critical evaluation for PVR. Currently, PVR is evaluated with invasive cardiac catheterization for hemodynamic data collection, processing, and analysis. Despite the limitation of hemodynamic evaluation in the setting of CHD, accurate data analysis, and interpretation have significant impact on clinical outcome and procedure success. This article reviews the basic calculation of PVR in the setting of congenital heart disease with diagrammatic illustration for easy understanding of the hemodynamic.

Aortic valve surgery for aortic regurgitation caused by Libman-Sacks endocarditis in a patient with primary antiphospholipid syndrome: a case report

Antiphospholipid syndrome is an antibody mediated pro-thrombotic state leading to various arterial and venous thromboses. The syndrome can be either primary or secondary to other autoimmune diseases. Cardiac involvement, in particular valvular disease is common in patients with antiphospholipid syndrome (APS) but it is frequently underestimated as most clinicians do not routinely screen for valvular lesion in patients with APS unless they are symptomatic. Valvular disease associated with antiphospholipid syndrome often occurs as valve thickening and non-bacterial vegetation or Libman-Sacks endocarditis, with a higher propensity towards mitral valve although haemodynamically significant valvular dysfunction is rare. Valve surgery in patients with APS carries considerable early and late morbidity and mortality, usually caused by thromboembolic and bleeding events. The perioperative anticoagulation management and haemostatic aspect of APS present exceptional challenges to clinicians, surgeons, anaesthetists and laboratory personnel. Thus, the indication of valve surgery and the choice of valve remains a critical consideration in these patients. We present a successful isolated aortic valve replacement with cardiopulmonary bypass in a 48 year old lady with newly diagnosed antiphospholipid syndrome, who has severe aortic regurgitation as a result of Libman-Sacks endocarditis. Antiphospholipid antibodies were positive and the clinical data showed both negative cultures and infective parameters. Surgically resected vegetations revealed sterile fibrin fibrinous and verrucous vegetations on aortic valve. Valve replacement and the course of cardiopulmonary bypass were uneventful, and patient was discharged well.

Image-Guided Adaptive Brachytherapy (IGABT) for Primary Vaginal Cancer: Results of the International Multicenter RetroEMBRAVE Cohort Study

Purpose: This study assessed outcomes following the nowadays standing treatment for primary vaginal cancer with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT) in a multicenter patient cohort. Methods: Patients treated with computer tomography (CT)–MRI-assisted-based IGABT were included. Retrospective data collection included patient, tumor and treatment characteristics. Late morbidity was assessed by using the CTCAE 3.0 scale. Results: Five European centers included 148 consecutive patients, with a median age of 63 years. At a median follow-up of 29 months (IQR 25–57), two- and five-year local control were 86% and 83%; disease-free survival (DFS) was 73% and 66%, and overall survival (OS) was 79% and 68%, respectively. Crude incidences of ≥ grade-three urogenital, gastro-intestinal and vaginal morbidity was 8%, 3% and 8%, respectively. Lymph node metastasis was an independent prognostic factor for disease-free survival (DFS). Univariate analysis showed improved local control in patients with T2–T4 tumors if >80 Gy EQD2α/β10 was delivered to the clinical target volume (CTV) at the time of brachytherapy. Conclusions: In this large retrospective multicenter study, IGABT for primary vaginal cancer resulted in a high local control with acceptable morbidity. These results compared favorably with two-dimensional (2D) radiograph-based brachytherapy and illustrate that IGABT plays an important role in the treatment of vaginal cancer.