Biomarkers in chronic graft-versus-host disease: quo vadis?

Biomarkers are increasingly used for diagnosis and treatment of transplant-related complications including the first biomarker-driven interventional trials of acute graft-versus-host disease (GvHD). In contrast, the development of biomarkers of chronic GvHD (cGvHD) has lagged behind due to a broader variety of manifestations, overlap with acute GvHD, a greater variation in time to onset and maximum severity, and lack of sufficient patient numbers within prospective trials. An international workshop organized by a North-American and European consortium was held in Marseille in March 2017 with the goal to discuss strategies for future biomarker development to guide cGvHD therapy. As a result of this meeting, two areas were prioritized: the development of prognostic biomarkers for subsequent onset of moderate/severe cGvHD, and in parallel, the development of qualified clinical-grade assays for biomarker quantification. The most promising prognostic serum biomarkers are CXCL9, ST2, matrix metalloproteinase-3, osteopontin, CXCL10, CXCL11, and CD163. Urine-proteomics and cellular subsets (CD4+ T-cell subsets, NK cell subsets, and CD19+CD21low B cells) represent additional potential prognostic biomarkers of cGvHD. A joint effort is required to verify the results of numerous exploratory trials before any of the potential candidates is ready for validation and subsequent clinical application.

NIH response criteria measures are associated with important parameters of disease severity in patients with chronic GVHD.

Lack of standardized criteria measuring therapeutic response remains an obstacle to the development of better treatments for chronic GVHD (cGVHD). This cross-sectional prospective study examined the concurrent and predictive validity of 18 clinician-reported ('Form A') and 8 patient-reported ('Form B') response measures proposed by NIH criteria. Concurrent parameters of interest were NIH global score, cGVHD activity, Lee symptom score and SF36 PCS. Patient cohort included 193 adults with moderate-to-severe cGVHD. Measures associated with the highest number of outcomes were lung function score (LFS), 2-min walk, grip strength, 4-point health-care provider (HCP) and patient global scores, 11-point clinician- and patient-reported global symptom severity scores, and Karnofsky performance score (KPS). Measures associated with survival in univariate analyses led to a Cox model containing skin erythema, LFS, KPS, eosinophil count and interval from cGVHD diagnosis to enrollment as jointly associated with survival. In conclusion, 4-point HCP and patient global scores and 11-point clinician- and patient-reported global symptom severity scores are associated with the majority of concurrent outcomes. Skin erythema is a potentially reversible sign of cGVHD that is associated with survival. These results define a subset of measures that should be prioritized for evaluation in future studies.

Malnutrition in patients with chronic GVHD.

Malnutrition is a known complication of chronic GVHD (cGVHD), but has not been well described in the context of organ-specific manifestations and the recent National Institutes of Health (NIH) criteria. Here, 210 cGVHD patients were analyzed, in a cross-sectional study design, for demographics, transplant-related history, clinical assessments, symptoms, function, quality-of-life, laboratory values and survival in order to determine their associations with nutritional status. Most patients had long-standing, moderate or severe cGVHD and had failed many lines of therapy. Twenty-nine percent (60/210) of subjects were malnourished, using the subjective Patient-Generated Subjective Global Assessment (PG-SGA) questionnaire and evaluation. No demographic or transplant characteristics were associated with malnutrition; cGVHD of the lungs, gastrointestinal (GI) tract and mouth, NIH global score, cGVHD symptoms, worse functioning, low albumin, poorer survival and low BMI were associated with malnutrition. A predictive model was developed from all variables of significance: cGVHD of the lungs, GI tract, mouth and BMI accurately predicted 84.2% of malnourished patients as well as 87.2% of well-nourished patients. The PG-SGA questionnaire may be a useful tool in diagnosing nutritional deficits in cGVHD patients undergoing one-time evaluations. Longitudinal prospective studies should assess the utility of nutritional support interventions in cGVHD.

NHANES III equations enhance early detection and mortality prediction of bronchiolitis obliterans syndrome after hematopoietic SCT.

Bronchiolitis obliterans syndrome (BOS) is a serious complication of chronic GVHD (cGVHD) following HSCT (hematopoietic SCT). The clinical diagnosis of BOS is based on pulmonary function test (PFT) abnormalities including: FEV1<75% predicted and obstructive FEV1/VC ratio, calculated using reference equations. We sought to determine if the frequency of clinical diagnoses and severity of BOS would be altered by using the recommended NHANES III vs older equations (Morris/Goldman/Bates, MGB) in 166 cGVHD patients, median age 48 (range: 12-67). We found that NHANES III equations significantly increased the prevalence of BOS, with an additional 11% (18/166) meeting diagnostic criteria by revealing low FEV1 (<75%) (P<0.0001), and six additional patients by obstructive ratio (vs MBG). Collectively, this led to an increase of BOS incidence from 17 (29/166) to 29% (41/166). For patients with severe BOS, (FEV1<35%), NHANES III equations correctly predicted death 71.4% vs 50% using MGB. In conclusion, the use of NHANES III equations markedly increases the proportion of cases meeting diagnostic criteria for BOS and improves prediction of survival.

Validation of the National Institutes of Health chronic GVHD Oral Mucosal Score using component-specific measures.

Oral chronic GVHD (cGVHD) is a common, late complication of alloSCT that is associated with significant patient morbidity. The NIH Oral Mucosal Score (NIH OMS) was developed to assess oral cGVHD therapeutic response, but has not been fully validated. This study's purpose was to conduct a rigorous construct validity and internal consistency analysis of this score and its components (erythema, lichenoid, ulcers, mucoceles) using established measures of oral pain, oral function, oral-related quality-of-life, nutrition and laboratory parameters in 198 patients with cGVHD. The construct validity of the NIH OMS was supported: a moderate correlation was observed between NIH OMS and mouth pain (rho=0.43), while a weaker correlation was observed with low albumin (rho=-0.26). Total NIH OMS, erythema and lichenoid components were associated with malnutrition, oral pain and impaired oral QOL, while ulcers were only associated with oral pain. No associations were found between mucoceles and any indicator evaluated, including salivary function or xerostomia. Kappa determined between scale components was low overall (all 0.35), supporting a conclusion that each component measures a distinct manifestation of oral cGVHD. This study supports the use of the NIH OMS and its components (erythema, lichenoid and ulcerations) to measure clinician-reported severity of oral cGVHD.

Active thrombopoiesis is associated with worse severity and activity of chronic GVHD.

Chronic GVHD (cGVHD) is a major complication of allogeneic hematopoietic SCT. Post transplant thrombocytopenia in patients with cGVHD has been associated with poor outcome and its etiology is unclear. We investigated whether thrombopoiesis, assessed via measurement of the absolute immature platelet number (AIPN) in the blood, is impaired in cGVHD, and whether the level of thrombopoiesis correlates with the severity and activity of cGVHD as assessed via the National Institutes of Health (NIH) organ scoring system. We used a cohort of 110 well-characterized cGVHD patients, including 83 (75%) with severe cGVHD per NIH global score. Higher AIPN was associated with active therapeutic intent (P=0.026), lower Karnofsky score (P=0.0013), worse joint/fascia cGVHD (P=0.0005) and worse skin cGVHD (P=0.0044). AIPN correlated with platelet counts and was not correlated with ANC, WBC, C-reactive protein (CRP), absolute lymphocyte count (ALC), albumin, total and average NIH scores, or number of prior systemic therapies. AIPN values for cGVHD patients substantially overlapped those of the normal population. Higher AIPN, as marker of active thrombopoiesisis, was associated with worse severity and activity of cGVHD, especially skin and joints/fascia manifestations. Among patients with stable moderate or severe cGVHD, there was no evidence of hypoproduction of platelets. Future studies should further investigate the role of thrombopoiesis in cGVHD.

Clinical laboratory markers of inflammation as determinants of chronic graft-versus-host disease activity and NIH global severity.

Chronic graft-versus-host disease (cGVHD) remains a major cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Currently there are no accepted measures of cGVHD activity to aid in clinical management and disease staging. We analyzed clinical markers of inflammation in the sera of patients with established cGVHD and correlated those with definitions of disease activity. In all, 189 adults with cGVHD (33% moderate and 66% severe according to National Institutes of Health (NIH) global scoring) were consecutively enrolled onto a cross-sectional prospective cGVHD natural history study. At the time of evaluation, 80% were receiving systemic immunosuppression and failed a median of four prior systemic therapies (PST) for their cGVHD. Lower albumin (P<0.0001), higher C-reactive protein (P = 0.043), higher platelets (P = 0.030) and higher number of PST (P<0.0001) were associated with active disease defined as clinician's intention to intensify or alter systemic therapy due to the lack of response. Higher platelet count (P = 0.021) and higher number of PST (P<0.0001) were associated with more severe diseased defined by NIH global score. This study identified common laboratory indicators of inflammation that can serve as markers of cGVHD activity and severity.

Thrombocytopenia and hemostatic disorders in chronic graft versus host disease.

Chronic graft versus host disease (cGVHD) is a major and frequent late complication in allogeneic stem cell transplantation recipients. Although thrombocytopenia in cGVHD patients is among the most consistent and strongest predictors of poor survival across many cGVHD studies, such correlation is still neither clearly explained nor well understood. Low platelet counts in the setting of cGVHD are associated with an increase in complications and treatment-related mortality, but usually not with higher relapse rate or engraftment failure rate. Bleeding might be occasionally increased along with, paradoxically, thrombosis. Hemostatic disorders in the context of cGVHD are significant complications with multifactorial etiology, including tissue injury with releasing microparticles, cytokine release, macrophage/monocyte clearance, CMV infection, production of transforming growth factor-beta, and low levels of thrombopoietin. Future clinical trials with agents that stimulate megakaryocytopoiesis or influence underlying impaired hemostasis mechanisms should investigate whether such interventions may improve outcomes in patients with cGVHD.

Paying tuition and academic performance of students at the Zagreb University School of Medicine.

AIM: To assess whether the prospect of waiving tuition fees influences the academic performance of the students with the lowest admission test scores and consequent mandatory tuition. METHODS: We compared the 110 tuition-paying students with the students who did not have to pay tuition because they scored well on 1994-1997 admission tests to the Zagreb School of Medicine. We formed 3 control groups (high-, medium-, and low-ranked students on the admission test), each with the same number of students as the group of tuition-paying students. Students' performance was assessed after the first two academic years on the basis of their grades, number of tries to pass the same examination, the time needed to pass an examination after a course, and the number of repeated years. RESULTS: Of 110 tuition-paying students admitted to the School in the 1994-1997 period, 13 had their tuition permanently waived and were therefore excluded from the analysis. Tuition-paying students had an the average grade of 3.1 out of maximum 5, took each examination 1.7 times before passing it, needed more than five months to pass an examination, and repeated 1.5 years per student. Their performance parameters did not differ from those of the low-ranked group, but were significantly worse than of the medium-ranked and high-ranked groups. Students in the high-ranked group performed the best in all four parameters (the average grade was slightly above 4.0, they took each examination 1.2 times on average, needed less than 2 months to pass an examination, and repeated 0.3 years per student). CONCLUSION: The prospect of waiving tuition fees had no influence on students' performance. The students' rank on the admission test strongly correlates with their later academic success.

Opinions of Zagreb University students on professor-student dating.

AIM: To investigate what Zagreb University students think about professor-student dating. METHODS: We surveyed 500 students from ten different Zagreb University schools using anonymous questionnaires. Twenty-five female and 25 male students from each school were asked to assess professor-student dating as either acceptable, reckless, unethical, or shameful, and decide how severely such behavior should be punished, if it should be punished at all. Sex of the professor and student was irrelevant. RESULTS: Students were equally strict towards the student and the professor. They judged professor-student dating more strictly if dating started before the student passed the exam in the subject taught by the professor than if it started afterwards. More female than male students had no opinion on whether the professor should be punished. When dating started after the student passed the exam, male students judged the student's behavior more strictly than female students; if the dating started before, the Economics students were stricter and the Music Academy students milder than average in their judgements. In the case when dating started after the student passed the exam, students of the Faculty of Physical Education judged both dating parties more strictly, Political Sciences students were milder toward a professor, whereas more students of the Faculty of Philosophy thought that it should be punished. Most students with no opinion on punishing dating were found among Agronomy students. CONCLUSION: Most Zagreb University students think that professor-student dating should not be punished and that both dating parties take equal responsibility for such behavior.

Curricular and extracurricular activities of medical students during war, Zagreb University School of Medicine, 1991-1995.

War, as a major human disaster, affects many aspects of life, including medical education. This report describes curricular and extracurricular activities of the students at the Zagreb University School of Medicine during the wars in Croatia and neighboring Bosnia and Herzegovina. Although condensed versions of the curricula were prepared in case of a major breakdown in civilian life, the school maintained the continuity and quality of its curriculum throughout the war. Students engaged in extracurricular activities related to medical aspects of the war, including organization of resuscitation and first aid courses, collecting medical documentation on war victims, humanitarian help to refugees, and peace-promoting activities. Some students joined mobile surgical teams on the battlefronts. After army service, most of them returned to the school and successfully continued with their studies. The school also accepted guest-students from other new states emerged from former Yugoslavia. The authors found that the students' engagement in extracurricular activities related to medicine was enormously beneficial both to the psychological well-being of the students and to the region's peace-building efforts.

[History of student medical journals at the Medical School of the University of Zagreb]. / Povijest studentskih medicinskih casopisa na Medicinskom fakultetu Sveucilista u Zagrebu.

The aim of the present study was to describe students' medical journals that have been edited by students of the Medical School of the University of Zagreb through history. Data were collected from the archives of the National and university library in Zagreb and from the Central library of the Medical School of the University of Zagreb. In 1925 in Zagreb was published the only number of "Medicinarski Vesnik--Glasilo Saveza medicinarskih drustava u Kraljevini SHS". In 1937-1938 in Zagreb were published eleven numbers of "Savremeni hrvatski medicinar--Casopis Kluba Medicinara Zagreb", then it ws forbidden. "Medicinar" has been published from 1946 till today. From 1958 to 1963 "Medicinar na Autoput" was published, and 1959 two numbers of "Ekscitator"--humoristic medical journal. From 1984 to 1987 the journal "Limfa" was published. During eighty years of the existence of the Medical School of the University of Zagreb, students have dignified work of the school by editing and publishing journals. Through "Medicinar"--the journal with the longest tradition and with major importance they do the same nowadays, contributing to the reputation and specialty of the school and the state as a whole.