Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma.

BACKGROUND: In the phase III HIMALAYA study (NCT03298451) in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) versus sorafenib; durvalumab monotherapy was noninferior to sorafenib for OS. Results reported herein are from a 4-year updated OS analysis of HIMALAYA. PATIENTS AND METHODS: Participants with uHCC and no previous systemic treatment were randomized to STRIDE (n = 393), durvalumab (n = 389), or sorafenib (n = 389). The updated data cut-off was 23 January 2023. OS and serious adverse events (AEs) were assessed. Additionally, baseline characteristics and subsequent therapies were analyzed in long-term survivors (≥36 months beyond randomization). RESULTS: For STRIDE, durvalumab, and sorafenib, median [95% confidence interval (CI)] follow-up was 49.12 months (46.95-50.17 months), 48.46 months (46.82-49.81 months), and 47.31 months (45.08-49.15 months), respectively. OS hazard ratio (95% CI) for STRIDE versus sorafenib was 0.78 (0.67-0.92). The 36-month OS rate for STRIDE was 30.7% versus 19.8% for sorafenib. The 48-month OS rate remained higher for STRIDE at 25.2%, versus 15.1% for sorafenib. The long-term OS benefit of STRIDE was observed across clinically relevant subgroups and was further improved in participants who achieved disease control. Long-term survivors with STRIDE (n = 103) included participants across clinically relevant subgroups, and 57.3% (59/103) had no reported subsequent anticancer therapy. No new serious treatment-related AEs occurred with STRIDE from the primary analysis (17.5%; 68/388). Durvalumab maintained OS noninferiority to sorafenib and no late-onset safety signals were identified. CONCLUSIONS: These data represent the longest follow-up to date in phase III studies in uHCC. The unprecedented 3- and 4-year OS rates reinforce the sustained long-term OS benefit of STRIDE versus sorafenib. STRIDE maintained a tolerable yet differentiated safety profile from other current uHCC therapies. Results continue to support the long-term benefits of STRIDE in a diverse population, reflective of uHCC globally.

[Hepatocellular carcinoma]. / Das hepatozelluläre Karzinom.

Hepatocellular carcinoma (HCC) is a highly malignant tumor and is the most common cause of death in patients with underlying liver cirrhosis. The main risk factor for development of HCC is liver cirrhosis. Because of the increasing frequency of nonalcoholic steatohepatitis, the incidence of HCC is also expected to considerably rise in Western countries in upcoming years. Identification and surveillance of patients at risk is crucial because curative treatment approaches can only be applied at early stages of the disease. Due to underlying liver cirrhosis, therapeutic strategies are limited and require intense interdisciplinary cooperation and multimodal approaches. However, a strong morphological and genetic heterogeneity of HCC remains a major challenge for development of new treatment modalities and demands personalized precision medicine approaches in order to improve patient outcome.

High-definition endoscopy with iScan and Lugol's solution for the detection of inflammation in patients with nonerosive reflux disease: histologic evaluation in comparison with a control group.

Nonerosive reflux disease (NERD) is commonly diagnosed in patients with symptoms of reflux. The aim of the present study was to determine whether high-definition endoscopy (HD) plus equipped with the iScan function or chromoendoscopy with Lugol's solution might permit the differentiation of NERD patients from those without reflux symptoms, proven by targeted biopsies of endoscopic lesions. A total of 100 patients without regular intake of proton pump inhibitors and with a normal conventional upper endoscopy were prospectively divided into NERD patients and controls. A second upper endoscopy was performed using HD+ with additional iScan function and then Lugol's solution was applied. Biopsy specimens were taken from the gastroesophageal junction in all patients. A total of 65 patients with reflux symptoms and 27 controls were included. HD(+) endoscopy with iScan revealed subtle mucosal breaks in 52 patients; the subsequent biopsies confirmed esophagitis in all cases. After Lugol's solution, 58 patients showed mucosal breaks. Sensitivity for the iScan procedure was 82.5%, whereas that for Lugol's solution was 92.06%. Excellent positive predictive values of 100% and 98.3%, respectively, were noted. The present study suggests that the majority of patients with NERD and typical symptoms of reflux disease can be identified by iScan or Lugol's chromoendoscopy as minimal erosive reflux disease (ERD) patients.

[Expert recommendations: Hepatitis C and transplantation]. / Empfehlungen zur antiviralen Therapie der chronischen Hepatitis C bei Patienten auf der Warteliste und nach Transplantation.

With the approval of new direct acting antiviral agents (DAA), therapeutic options for patients with chronic hepatitis C virus (HCV) infection are now generally available before and after liver transplantation (LT). Interferon-free DAA regimens are highly effective therapies and provide a good safety profile. However, the body of clinical evidence in this patient population is limited and the best treatment strategies for patients on the waiting list with (de)compensated cirrhosis and after LT are not well defined. The following recommendations for antiviral therapy in the context of LT are based on the currently available literature and clinical experience of experts in the field, and have been discussed in an expert meeting. The aim of this article is to guide clinicians in the decision making when treating patients before and after LT with DAAs.

Lack of awareness in both patients and physicians contributes to a high rate of late presentation in a South West German HIV patient cohort.

PURPOSE: To assess rate of late presentation with HIV in Southwestern Germany and to identify patient characteristics correlated with CD4 nadir. METHODS: Patients with primary diagnosis who presented to one of ten participating clinics rated on knowledge and behavior towards HIV testing on a self-developed questionnaire, whereas clinical data was assessed by the physician. RESULTS: 161 patients were included. Risk factors were homosexual (59.5 %) or heterosexual contacts (26.8 %), drug use (2.0 %), migration (3.9 %), or others (7.8 %). 63.5 % had a CD4 T cell count < 350/µl. 52.5, 17.4, and 31.1 % were diagnosed in CDC stadium A, B or C, respectively. 209 disease episodes were reported, from whom 83.7 % had led to the diagnosis of HIV. 75.2 and 68.3 % said to have been well-informed about ways of transmission and testing offerings, respectively, and 20.4 % admitted to have psychologically repressed the possibility of being infected. 48 patients rated their personal behavioral risk as "high" or "very high". Of these, however, only ten had performed at test in the precedent year. Performing a regression analysis, younger age and previous testing were correlated with a higher CD4 T cell nadir (p = 0.005, and 0.018, resp.). CONCLUSION: The rate of late presentation in this region was even higher compared to national or European surveys. Most infected patients perceived to have had only a low risk. Several disease episodes did not lead to the initiation of HIV testing by the physician.

[Cost-effective medical therapy of hepatitis C employing novel compensation models - pay for cure]. / Kosteneffiziente medikamentöse Therapie der Hepatitis C durch neue Vergütungsmodelle - pay for cure.

Direct acting antivirals (DAAs) have increased cure rates for chronic hepatitis C infection up to nearly 100 %. At the same time treatment costs have risen significantly. Treating all HCV infected patients in Germany with DAAs would generate medication costs ranging between 19 and 37 billion EUR depending on the drug regimen used. Expenses in patients who fail to respond to treatment would amount to approximately 0.9 to 2.15 billion EUR. In difficult to treat patient populations that are characterized by prior failure to treatment or advanced liver disease, lost drug expenses are particularly high due to lower cure rates and longer treatment duration. Outcome-based reimbursement schemes are used to improve the quality of care and to reduce costs in the health care system. In Germany, disease management programs have been implemented for defined chronic diseases. However, drug reimbursement is still based on packages sold (pay for pill). In this context, it would be appealing to link reimbursement and treatment success (pay for cure) in order to reward successful treatment, limit lost drug spending and develop a shared risk environment that would involve all concerned parties. Under the assumption that 20,000 patients with HCV are treated each year in Germany and that cure rates are 95.4 %, the saved treatment costs would amount up to 45 and 107 million EUR per year. By this approach, economic incentives to withhold therapy from difficult to treat patients could be avoided.

Hepatitis B virus-specific T-cell responses during IFN administration in a small cohort of chronic hepatitis B patients under nucleos(t)ide analogue treatment.

The effect of pegylated interferon-α (IFN) add-on therapy on HBV-specific T-cell responses was evaluated in 12 patients with stable, undetectable hepatitis B virus (HBV) load under nucleos(t)ide analogue therapy. Peripheral blood mononuclear cells were isolated at week 0, 4, 8, 12, 24 and 48 of IFN add-on therapy. Quantity and quality of circulating HBV S- and core-specific CD4 and CD8 T cells were analysed ex vivo by flow cytometry. HBV S- and core-specific CD4 T-cell numbers modestly increased within 8 weeks of IFN administration (P = 0.0391 and P = 0.0195), whereas HBV-specific CD8 T cells in general showed only minor changes under IFN add-on therapy. Functionality of HBV-specific CD4 but not CD8 T cells positively correlated with serum transaminase activity. In addition, we observed an increase in CD4 T cells producing tumour necrosis factor-α (TNFα) without antigen restimulation (P = 0.0039), which correlated with elevated transaminases. During IFN add-on therapy, two patients developed an anti-HBs seroconversion, only one of whom showed a relevant increase in HBV-specific T cells. In conclusion, IFN add-on therapy of chronic hepatitis B increased HBV-specific T-cell responses and affected a previously unrecognized TNFα-monofunctional CD4 T-cell population. Although the observed T-cell responses did not correlate with HBsAg seroconversion, we expect additional insights into the immunopathogenesis of hepatitis B, following the characterization of the newly identified TNF α-monofunctional T-cell population.

Preoperative left ventricular hypertrophy is associated with reduced patient survival after liver transplantation.

UNLABELLED: Left ventricular hypertrophy (LVH) has been described in the context of cirrhotic cardiomyopathy. The influence of LVH on survival of liver transplant (LT) recipients has not been clarified. Therefore, we evaluated the effect of LVH on survival in LT recipients. In total, data from 352 LT patients were analyzed. LVH was diagnosed by echocardiographic measurement of left ventricular wall thickness before LT. Patients were followed up for a mean of 4.2 yr. LVH was diagnosed in 135 (38.4%) patients. Patients with LVH had significantly more frequently male gender (p = 0.046), diastolic dysfunction (p < 0.001), and hepatocellular carcinoma (HCC; p = 0.004). Furthermore, LVH patients were older (p < 0.001) and had a higher body mass index (BMI; p = 0.001). There was no difference in frequency of arterial hypertension, pre-transplant diabetes mellitus, or etiology of liver cirrhosis. Patients without LVH had a better survival (log rank: p = 0.05) compared with LVH patients. In a multivariate Cox regression LVH (p = 0.031), end-stage renal disease (ESRD; p = 0.003) and lack of arterial hypertension (p = 0.004) but not MELD score (p = 0.885) were associated with poorer survival. CONCLUSION: LVH is frequently diagnosed in patients on the waiting list and influences survival after LT.

Successful treatment of Erdheim-Chester disease with combination of interleukin-1-targeting drugs and high-dose glucocorticoids.

Erdheim-Chester disease (ECD) is a rare histocytic disorder. We report a case of a 45-year-old male ECD patient with severe clinical manifestation (urinary obstruction due to retroperitoneal mass with hydronephrosis, involvement of long bones) and central nervous system involvement (hemiparesis, aphasia and diabetes insipidus). Diagnosis was confirmed by typical clinical, radiological and histological findings. Under immunosuppressive therapy with prednisolone and interleukin-1A receptor antagonist (Anakinra, Kineret, Swedish Orphan Biovitrum AB, Stockholm, Sweden), a rapid improvement of the patients' symptoms and condition was observed. This is the first report of a successful combination therapy of Anakinra and glucocorticoids. Furthermore, current literature about ECD and treatment options are discussed.

[Drug-induced liver injury with an autoimmune phenotype following anti-TNF Therapy - presentation of cases and review of literature]. / Medikamentöse Schädigung der Leber mit autoimmunem Phänotyp durch TNF-Blockade - Fallvorstellung und Review der Literatur.

Therapeutic agents to inhibit tumour necrosis factor alpha (TNF-α) have dramatically improved the treatment options for patients with autoimmune diseases. Common side effects include an increased susceptibility towards infection. Hepatic side effects are less frequently observed. Elevated liver function tests, hyperbilirubinaemia reactivation of chronic viral hepatitis or even acute liver failure have been described. Some cases have exhibited an autoimmune phenotype with the emergence of autoantibodies and characteristic histological lesions. We report on three patients who received anti-TNF therapy for psoriasis and presented with elevated liver function tests in the further course. Histological and serum analysis revealed an autoimmune phenotype of liver injury. In light of the growing use of anti-TNF therapies, drug-induced liver injury (DILI) with an autoimmune phenotype is an important side effect. Since the pathophysiological mechanisms related to the autoimmune phenotype of liver injury during TNF-inhibition are not well understood, the cases detailed herein should help treating physicians to improve their understanding of the situation.

[Upper gastrointestinal bleeding and haemorrhagic shock at the end of the holidays: pre-hospital and in-hospital management of a gastrointestinal emergency]. / Obere gastrointestinale Blutung mit hämorrhagischem Schock am Ende einer Urlaubsreise: Präklinische und innerklinische Versorgung eines gastrointestinalen Notfalls.

Upon returning from holidays, a 55-year-old patient presenting with melena and haemorrhagic shock was admitted to a University hospital after receiving first emergency medical care in a German InterCity train. In an interdisciplinary effort, haemodynamics were stabilised and the airway and respiratory function were secured. Under emergency care conditions the patient then underwent an emergency upper GI endoscopy where a spurting arterial upper gastrointestinal bleeding (Forrest 1a) was found. While the bleeding could not be controlled with endoscopic techniques, definitive haemostasis was achieved with a surgical laparotomy. While not commonly established for patients with severe GI bleeding, by spontaneous implementation of an interdisciplinary trauma room approach following established trauma algorithms the team was able to achieve stabilisation of vital functions and final control of bleeding in this highly unstable patient. Although the majority of upper gastrointestinal bleedings spontaneously cease, emergency care algorithms should be developed and implemented for patients with severe gastrointestinal bleedings in shock. Following the case vignette, we discuss a potential approach and develop an exemplary protocol for shock room management in this patient subgroup.

[Therapy of hepatocellular carcinoma]. / Therapie des hepatozellulären Karzinoms.

Today, hepatocellular carcinoma (HCC) represents the leading cause of death in patients with liver cirrhosis; in most western countries the incidence is also expected to increase further. Due to insufficient surveillance of patients at risk, most cases are diagnosed in an intermediate to advanced stage, leading-together with the underlying liver cirrhosis-to limited therapeutic options and a dismal prognosis. Therefore, classification according to stage and interdisciplinary treatment decisions in experienced centers are of paramount importance to provide an individualized treatment plan when considering potentially curative (resection, liver transplantation, local ablation) and palliative (transarterial approaches, sorafenib) treatment options. There is hope that the prognosis of patients with HCC can be improved in the near future by better prevention, stringent surveillance, multimodality treatment approaches, and an expansion of personalized medicine.

Melatonin induces transcriptional regulation of Bim by FoxO3a in HepG2 cells.

BACKGROUND: Melatonin induces apoptosis in many different cancer cell lines, including hepatocellular carcinoma cells. However, the responsible pathways have not been clearly elucidated. A member of the forkhead transcription factors' family, FoxO3a, has been implicated in the expression of the proapoptotic protein Bim (a Bcl-2-interacting mediator of cell death). In this study, we used human HepG2 liver cancer cells as an in vitro model to investigate whether melatonin treatment induces Bim through regulation by the transcription factor FoxO3a. METHODS: Cytotoxicity of melatonin was compared in HepG2 hepatoblastoma cells and primary human hepatocytes. Proapoptotic Bim expression was analysed by reverse transcriptase-polymerase chain reaction and western blot. Reporter gene assays and chromatin immunoprecipitation assays were performed to analyse whether FoxO3a transactivates the Bim promoter. Small interfering RNA (siRNA) was used to study the role of FoxO3a in Bim expression. Immunofluorescence was performed to analyse FoxO3a localisation in HepG2 cells. RESULTS: Melatonin treatment induces apoptosis in HepG2 cells, but not in primary human hepatocytes. The proapoptotic effect was mediated by increased expression of the BH3-only protein Bim. During melatonin treatment, we observed increased transcriptional activity of the forkhead-responsive element and could demonstrate that FoxO3a binds to a specific sequence within the Bim promoter. Furthermore, melatonin reduced phosphorylation of FoxO3a at Thr(32) and Ser(253), and induced its increased nuclear localisation. Moreover, silencing experiments with FoxO3a siRNA prevented Bim upregulation. CONCLUSION: This study shows that melatonin can induce apoptosis in HepG2 hepatocarcinoma cells through the upregulation of proapoptotic Bim mediated by nuclear translocation and activation of the transcription factor FoxO3a.

In vivo molecular imaging with cetuximab, an anti-EGFR antibody, for prediction of response in xenograft models of human colorectal cancer.

BACKGROUND AND STUDY AIMS: Molecular imaging has mainly been studied for detection of lesions using diagnostic probes. The aim of the current trial was to evaluate in vivo confocal laser endomicroscopy (CLE) with cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), for detection and moreover early prediction of response to molecular chemotherapy in models of human colorectal cancer (CRC). METHODS: Xenografts with cetuximab-sensitive (HT29) and cetuximab-resistant (SW620) human CRC cell lines were induced in 44 mice. CLE was performed 48 h after injection of a fluorescently labelled cetuximab test dose, and compared with isotype antibody or untreated controls on d0, and d30 (HT29) or d15 (SW620). Initial fluorescence intensity was examined in relation to clinical readouts (tumor growth, thriving, mortality) during cetuximab treatment vs. controls. Results were validated in vivo with wide-field molecular imaging in three HT29 mice and ex vivo using fluorescence-activated cell sorting (FACS) and immunohistochemistry. RESULTS: All HT29 xenografts showed specific fluorescence in vivo after cetuximab injection on d0 and d30. Fluorescence at d0 was significantly stronger in cetuximab-treated HT29 tumors than in HT29 controls (P = 0.0017) or cetuximab-treated SW620 tumors (P = 0.0027), and accorded with significantly slower tumor progression (P = 0.0009), better overall survival (P = 0.02), and better physical condition (P < 0.0001). Cetuximab sensitivity could be predicted from fluorescence intensity at d0 with high positive predictive value. CONCLUSIONS: Molecular CLE was for the first time linked to early prediction of response to targeted therapy in models of human CRC. Therapeutic antibodies can be used as molecular beacons in CLE and wide-field techniques. These results may indicate a promising principle for early patient stratification.

Gastrointestinal disorders and dabigatran.

Anticoagulants play an important role in the prevention and treatment of a variety of acute and chronic thromboembolic disorders such as primary prevention and treatment of venous thromboembolism or prevention of stroke and systemic embolism in atrial fibrillation just to name of few. Within recent years, a promising new oral anticoagulant, the direct thrombin inhibitor dabigatran etexilate (dabigatran) successfully underwent clinical development and has emerged as an alternative to vitamin K antagonists according to a variety of recently revised and updated international guidelines referring to the indication of stroke prevention in atrial fibrillation. Considering the intensive clinical use of vitamin K antagonists in the mentioned indication as well as the widespread and increasing therapeutic need on one hand and the likely availability of a more efficacious alternative with fewer limitations in clinical practice on the other, there is good reason to assume that the use of dabigatran may be broad within the general medical community in the near future. Based on what is currently published in the public domain and clinical trial data it is suggested that dabigatran etexilate is associated with higher rates of dyspeptic symptoms compared to warfarin. Therefore, it is the authors' intent to review and discuss this potential dyspeptic side effect profile of dabigatran and potential counter measures from a gastroenterologist's perspective.

Disclosure behaviour and experienced reactions in patients with HIV versus chronic viral hepatitis or diabetes mellitus in Germany.

Disclosure is a prerequisite to receive disease-specific social support. However, in the case of a stigmatised disease, it can also lead to discrimination. We aimed to assess disclosure rates of HIV patients and the reactions they encountered in comparison to patients with chronic viral hepatitis or diabetes mellitus and patients' general perception of disease-specific discrimination. We constructed a self-report questionnaire, anonymously assessing the size of the social environment, the persons who had been informed, and the experienced reactions as perceived by the disclosing patients, to be rated on 1-4 point Likert scales. In addition, patients were asked whether they perceive general discrimination in Germany. One hundred and seventy-one patients were asked to participate. Five rejected, thus questionnaires from 83 patients with HIV, 42 patients with chronic viral hepatitis B (n = 9) or C (n = 33), and 41 patients with insulin-dependent diabetes mellitus (type I n = 14, type II n = 27) were analysed. Whereas the size of the social environment did not differ, HIV-infected patients were least likely to disclose their disease (60.7%, SD ± 31.9) to their social environment as compared to patients with chronic viral hepatitis (84.2 ± 23.3%, p<0.0001), or diabetes mellitus (94.4 ± 10.3%, p<0.0001), respectively. Within the HIV patient group, the mean disclosure rate was highest to partners (90.9%), followed by the public environment (65.2%), friends (59.4%) and family members (43.8%). HIV patients experienced supportive reactions after 79.3 ± 26.4% of disclosures, which was the case in 91.4 ± 19.6% and 75.7 ± 36.1% of patients with hepatitis or diabetes mellitus, respectively. 69.5% of HIV patients stated to perceive general discrimination in Germany. We conclude that HIV patients had experienced supportive reactions after the majority of disclosures, but the low rate points out that their information strategy had been very selective. Societal discrimination of HIV patients is still an issue and needs to be further addressed.

[Diagnosis of and therapy for hepatocellular carcinoma]. / Diagnostik und Therapie des hepatozellulären Karzinoms.

The interdisciplinary guidelines at the S3 level on the diagnosis of and therapy for hepatocellular carcinoma (HCC) constitute an evidence- and consensus-based instrument that is aimed at improving the diagnosis of and therapy for HCC since these are very challenging tasks. The purpose of the guidelines is to offer the patient (with suspected or confirmed HCC) adequate, scientifically based and up-to-date procedures in diagnosis, therapy and rehabilitation. This holds not only for locally limited or focally advanced disease but also for the existence of recurrences or distant metastases. Besides making a contribution to an appropriate health-care service, the guidelines should also provide the foundation for an individually adapted, high-quality therapy. The explanatory background texts should also enable non-specialist but responsible colleagues to give sound advice to their patients concerning specialist procedures, side effects and results. In the medium and long-term this should reduce the morbidity and mortality of patients with HCC and improve their quality of life.

[Interdisciplinary approach in a patient with IgG4-associated Mikulicz's disease]. / Interdisziplinäres Vorgehen bei einem Patienten mit IgG4-assoziiertem Morbus Mikulicz.

The clinical picture of enlarged submandibular gland and/or enlarged lacrimal gland often leads to difficulties in differential diagnostics. From the perspective of rheumatology Sjögren's syndrome should be excluded especially in patients who complained of xerophthalmia and xerostomia for longer than 3 months. In this article the authors report the case of a patient who presented to clarify swelling of the submandibular gland and xerostomia. In close cooperation with rheumatologists, otolaryngologists and pathologists the diagnosis of IgG4-associated sialoadenitis (IgG4-associated Mikulicz's disease) could be reached.

Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease.

OBJECTIVES: Loss of intestinal barrier function plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Shedding of intestinal epithelial cells is a potential cause of barrier loss during inflammation. The objectives of the study were (1) to determine whether cell shedding and barrier loss in humans can be detected by confocal endomicroscopy and (2) whether these parameters predict relapse of IBD. METHODS: Confocal endomicroscopy was performed in IBD and control patients using intravenous fluorescein to determine the relationship between cell shedding and local barrier dysfunction. A grading system based on appearances at confocal endomicroscopy in humans was devised and used to predict relapse in a prospective pilot study of 47 patients with ulcerative colitis and 11 patients with Crohn's disease. RESULTS: Confocal endomicroscopy in humans detected shedding epithelial cells and local barrier defects as plumes of fluorescein effluxing through the epithelium. Mouse experiments demonstrated inward flow through some leakage-associated shedding events, which was increased when luminal osmolarity was decreased. In IBD patients in clinical remission, increased cell shedding with fluorescein leakage was associated with subsequent relapse within 12 months after endomicroscopic examination (p<0.001). The sensitivity, specificity and accuracy for the grading system to predict a flare were 62.5% (95% CI 40.8% to 80.4%), 91.2% (95% CI 75.2 to 97.7) and 79% (95% CI 57.7 to 95.5), respectively. CONCLUSIONS: Cell shedding and barrier loss detected by confocal endomicroscopy predicts relapse of IBD and has potential as a diagnostic tool for the management of the disease.