Years Of Clinical Remission Research Articles

Immunotherapy withdrawal by step-down to mesalamine in pediatric patients with ulcerative colitis.

Parents and pediatric patients with ulcerative colitis (UC) who progressed to systemic immunotherapy are concerned about lifelong risks from such treatments. There is limited knowledge about withdrawal of such agents and step-down (SD) to enteral 5-aminosalicylic acid(mesalamine) before transitioning to adult care. We studied nine pediatric cases with moderate to severe UC whoafter a median of 2.18 years of clinical remission on systemic immunotherapy stepped down to oral mesalamine treatment. Average follow-up time from SD was 3.49 years. Five patients (55.5%) had sustained remission (without any flare noted) after SD during follow-up. Sustained clinical remission was 88.9% (8/9) at 1 year, 87.5% (7/8) at 2 years, and 66.7% (4/6) at 3 years after SD. Out of those tested (one patient was not tested), 62.5% (5/8) had fecal calprotectin <50 μg/g. Four out of six patients examined (66.6%) had mucosal healing on post-SD colonoscopy. We propose that SD to mesalamine can be a reasonable therapeutic consideration for pediatric patients with UC before transitioning to adult gastroenterology care. Shared decision-making is important before such treatment changes.

Acute pulmonary edema caused by a multiple sclerosis relapse

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) [1]. In the majority of patients, MS begins with a relapsing–remitting course. It is characterized by unpredictable relapses followed by periods of months to years of clinical remission. MS relapses entail various clinical symptoms depending on the location of the inflammatory lesion within the CNS. Besides the common symptoms of optic neuritis, paresis, paraesthesia, and ataxic gait disorders, in some rare cases a relapse may alter cardiovascular and autonomic function [1]. Clinical studies have shown that acute cerebral lesions (e.g., stroke, hemorrhage) may induce changes in cardiac and respiratory function including hypertension, arrhythmias, myocardial necrosis, and sudden death [2, 3]. Moreover, experimental and clinical studies indicate that damage of the brainstem is likely to cause disturbances in either sympathetic or parasympathetic autonomic function with subsequent cardiac and respiratory dysfunction [4–6]. Neurogenic pulmonary edema (NPE) is usually defined as an acute pulmonary edema occurring shortly after various injuries of the central nervous system [7]. The most important vasomotor centers for NPE development are nuclei of the solitary tract, the dorsal motor vagus nucleus in the medulla oblongata and the medial reticulated nucleus. On the other hand, brainstem damage in the region of the solitary tract nuclei may result in a transient cardiomyopathy [8]. The exact mechanisms remain poorly understood because of the complexity of its pathophysiologic mechanisms, involving both hemodynamic and inflammatory aspects. There are two possible explanations: one presumes that neurological damage directly involves the pulmonary and cardiac vascular bed with disconnection of the central nervous system vasomotor centers. However, there are also data that brainstem dysfunction can cause changes of sympathetic vasomotor tone [7]. This case study describes a rare initial presentation of a MS relapse with pulmonary edema caused by left ventricular failure. A 48-year-old woman, diagnosed with clinically definite relapsing–remitting MS 3 years previously with a preexisting expanded disability status scale (EDSS) of 3.5, presented with increasing dyspnea and cough without chest pain to a department of internal medicine. She was on immunomodulatory treatment with glatiramer acetate. No clinically apparent atherosclerotic disease was known. On admission, laboratory testing showed that high-sensitivity troponin T was slightly elevated. An electrocardiogram showed no signs of myocardial infarction. In a coronary computed tomography angiogram, no significant changes in the coronary arteries were found. The next day, increases in high-sensitivity troponin T, C-reactive protein (CRP), and a massive increase of B-type natriuretic peptide (proBNP) were observed (Table 1). Pulmonary edema was initially not diagnosed (Fig. 1a) and according to the assumption of pneumonia the patient was treated with antibiotic therapy (amoxicillin) and furosemide. Due to the further worsening of respiratory conditions, intubation and mechanical respirator treatment became necessary. An echocardiogram showed acute left ventricular failure with apical wall motion abnormalities and a left ventricular ejection fraction of 35% in this patient without a history of cardiac disease. No abnormalities concerning the right ventricle and the atria were seen. With regard to her P. Wipfler (&) G. Pilz E. Broussalis S. M. Golaszewski A. Kunz E. Trinka J. Kraus Christian-Doppler-Klinik, University Hospital of Neurology, Paracelsus Medical University and Salzburger Landesklinken, Ignaz Harrerstrasse 79, 5020 Salzburg, Austria e-mail: p.wipfler@salk.at

Dominance of Nonmalignant T-Cell Clones and Distortion of the TCR Repertoire in the Peripheral Blood of Patients with Cutaneous CD30+ Lymphoproliferative Disorders

The CD30-positive cutaneous lymphoproliferative disorders (CLPD) include lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large T-cell lymphoma (cALCL). Despite the malign-appearing histology, an excellent prognosis and spontaneous regression of single lesions characterize LyP. Even after years of clinical remission newly erupting lesions often harbor a T-cell clone identical to the initial one. This fact raises the question whether the clonal T-cell population persists in the peripheral blood. Therefore we investigated genomic DNA of 126 samples of lesional skin and peripheral blood from 31 patients with CLPD, obtained during both active disease and clinical remission. We performed molecular genetic analysis by combining T-cell receptor (TCR)-gamma PCR with the GeneScan technique and assessed the TCR repertoire in selected blood samples by beta-variable complementarity-determining region 3 (CDR3) spectratyping qualitatively and quantitatively. We were able to detect a clonal T-cell population in 36/43 (84%) skin samples and in 35/83 (42%) blood samples. Comparison of the compartments in each patient demonstrated different T-cell clones in skin and blood, suggesting a reactive nature of the clonal T cells in the blood. Moreover, CDR3 spectratyping revealed a restricted T-cell repertoire in the blood, suggesting T-cell stimulation by an unknown antigen.

Genetic Reconstruction of Follicular Lymphoma Evolutions: Sμ Mutations Studies Suggest Two Progression Patterns, Early Direct or Late from FL “Stem Cells”.

Follicular lymphoma (FL) is characterised by recurrent relapses. Its clinical behaviour suggests that FL cells progressively gain proliferation advantages and evade therapies, probably by accumulating genetic alterations. However, VDJ mutations showed that, instead of a linear evolution, some relapses may develop from minor subclones, different from those that dominated at time of diagnosis. Unfortunately, this technically demanding approach could only be applied to few patients with limited sets of sequential biopsies. To re-address this issue, we developed an original tumour and allele specific assay to analyze the mutations that accumulate on the switch μ on the der(14)t(14;18) upon class switch recombination (CSR) activation. These mutations were compared between biological samples obtained in different sites during follow up. Fifty patients were studied, and 169 biological samples analysed (86 lymph nodes (LN), 45 peripheral blood samples (PB), and 38 bone marrow samples (BM)). For 48 patients, clonal mutations were found in all samples. However, we observed frequent intra-clonal variations (in 25 LN; 17 BM and 19 PB) and frequent differences between LN and BM (9/17), LN and PB (9/21) and even PB and BM (9/18) obtained at short time intervals (<1 month). These results indicate that FL is often a heterogeneous disease where different t(14;18) positive subclones spread or proliferate asymmetrically in and between tumoral compartments. They also suggest that CSR remains active after the acquisition of the transformed phenotype. However, in spite of this apparent ongoing CSR activity, the comparison of serial LN biopsies did not show any significant accumulation of mutations over time: 36 paired LN, median interval between biopsies: 32 months, 370 vs 363 mutation in all 1st and 2nd LNs respectively, median 7.5 vs 7 mutations/LN, p=0.89. Surprisingly, a simple apparition of new mutations was only observed once. For all other pairs, either mutations remained identical (14 cases), or their evolutions suggested complex selection schemes, sometimes apparently from subclones from another tumoral compartment. Notably, when mutations were identical, the second biopsy had almost always been obtained in less than 3 years (13/14 pairs). This strikingly contrasts with paired biopsies obtained at intervals of 3 years or more in which significant differences were almost always seen (14/15 pairs). This correlation between the evolution of the mutations and the interval between biopsies thus suggests different progression patterns. Finally, in many cases, mutations observed in the first LNs were not found at the following relapses (12/36 pairs). This observation confirms that many relapses do not develop from the dominant subclones at diagnosis but from less mutated ones. In conclusion, our results suggest that there may be at least two different patterns of progression in FL. The first could be a direct and rapid evolution from the dominant subclone, explaining the stability of the mutations. The second, which could potentially happen after many years of clinical remission, could instead be indirect, from a clonally related and often earlier t(14;18) positive subclone probably arising from a different compartment.

G-Coupled Protein Receptors and Breast Cancer Progression: Potential Drug Targets

Breast cancer remains a leading cause of death despite early screening and advances in medicine. Bone marrow metastasis often complicates the clinical picture by requiring more aggressive treatment and worsening long-term prognoses. Recent therapeutic targeting of hormonal receptors such as human epidermal growth factor receptor 2 and estrogen receptor has shown limited success in treating localized disease for those patients whose cancer cells are responsive. Although traditional approaches such as chemotherapy have demonstrated many successes, these agents fail to target quiescent cancer stem cells, which might have entered the bone marrow where they might be responsible for the quiescence population. Following years of clinical remission, these dormant cells could lead to secondary cancer resurgence. To date, little progress has been made in the development of targeted treatments for receptor negative and metastatic disease. In this review, we discuss the role of G-protein coupled receptors, including neurokinin-1, neurokinin-2 and chemokine receptor 4, as novel targets in the treatment of breast cancer.

Acute Promyelocytic Leukemia: Clinical Relevance of Two Major PML-RARα Isoforms and Detection of Minimal Residual Disease by Retrotranscriptase/Polymerase Chain Reaction to Predict Relapse

Recent data have shown that the PML-RAR alpha fusion gene resulting from translocation t(15;17) is a highly reliable molecular marker of acute promyelocytic leukemia (APL). In this study performed on 97 Chinese patients with APL, the retrotranscriptase/polymerase chain reaction (RT/PCR) was used to evaluate the clinical relevance of the long (L) or short (S) PML-RAR alpha fusion mRNA isoforms and to study minimal residual disease during clinical remission (CR). There were more early deaths during the all-trans retinoic acid (ATRA) induction treatment and more relapses within 2 years of CR in the S-type (6 of 19 cases) than in the L-type group (2 of 33 cases) (P < .025). Among 12 cases analyzed before and after the ATRA-induced CR, 9 cases (75%) showed positive RT/PCR, whereas only 3 cases showed a negative result, justifying the need for chemotherapy after ATRA-induced CR. Eleven of 62 APL patients in CR, after ATRA-induced CR and chemotherapy consolidation (follow-up, from 3 to 72 months), showed positive RT/PCR. Five of them relapsed within 1 to 6 months after the positive test; one converted to negative after further chemotherapy; and 5 remained in CR status without further PCR data. However, the latter 5 cases all received further intensive consolidation therapy after the PCR positivity. These results show that a positive RT/PCR of PML-RAR alpha is a sensitive predictor of relapse in APL.

Acute promyelocytic leukemia: clinical relevance of two major PML-RAR alpha isoforms and detection of minimal residual disease by retrotranscriptase/polymerase chain reaction to predict relapse

Recent data have shown that the PML-RAR alpha fusion gene resulting from translocation t(15;17) is a highly reliable molecular marker of acute promyelocytic leukemia (APL). In this study performed on 97 Chinese patients with APL, the retrotranscriptase/polymerase chain reaction (RT/PCR) was used to evaluate the clinical relevance of the long (L) or short (S) PML-RAR alpha fusion mRNA isoforms and to study minimal residual disease during clinical remission (CR). There were more early deaths during the all-trans retinoic acid (ATRA) induction treatment and more relapses within 2 years of CR in the S-type (6 of 19 cases) than in the L-type group (2 of 33 cases) (P &lt; .025). Among 12 cases analyzed before and after the ATRA-induced CR, 9 cases (75%) showed positive RT/PCR, whereas only 3 cases showed a negative result, justifying the need for chemotherapy after ATRA-induced CR. Eleven of 62 APL patients in CR, after ATRA-induced CR and chemotherapy consolidation (follow-up, from 3 to 72 months), showed positive RT/PCR. Five of them relapsed within 1 to 6 months after the positive test; one converted to negative after further chemotherapy; and 5 remained in CR status without further PCR data. However, the latter 5 cases all received further intensive consolidation therapy after the PCR positivity. These results show that a positive RT/PCR of PML-RAR alpha is a sensitive predictor of relapse in APL.