Clinical Signs Of Disease Progression Research Articles

Landscape of BCL2 Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax

The oral, highly selective Bcl2 inhibitor venetoclax has substantially improved the therapeutic landscape of chronic lymphocytic leukemia (CLL). Despite the remarkable response rates in patients with relapsed/refractory (R/R) disease, acquired resistance is the leading cause of treatment failure, with somatic BCL2 mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common BCL2 mutations G101V and D103Y, sensitive (10-4) screening for the most common BCL2 mutations G101V and D103Y was performed in 67 R/R CLL patients during venetoclax single-agent or venetoclax-rituximab combination therapy. With a median follow-up time of 23 months, BCL2 G101V and D103Y were detected in 10.4% (7/67) and 11.9% (8/67) of the cases, respectively, with four patients harboring both resistance mutations. Ten out of eleven patients carrying BCL2 G101V and/or D103Y experienced relapse during the follow-up period, representing 43.5% of the cases (10/23) showing clinical signs of disease progression. All BCL2 G101V or D103Y variants were detected in patients receiving venetoclax as a continuous single-agent treatment while these mutations were not observed during or after fixed-duration venetoclax therapy. Targeted ultra-deep sequencing of BCL2 uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of BCL2 mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which BCL2 resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for BCL2 resistance mutations in R/R CLL.

ANTISYNTHETASE SYNDROME PRESENTING AS INTERSTITIAL LUNG DISEASE: A CASE OF ANCHORING BIAS DURING THE COVID-19 PANDEMIC

ANTISYNTHETASE SYNDROME PRESENTING AS INTERSTITIAL LUNG DISEASE: A CASE OF ANCHORING BIAS DURING THE COVID-19 PANDEMIC

PB1871: PROGNOSTIC SIGNIFICANCE OF THE NOTCH1 GENE MUTATION AND OTHER LABORATORY FACTORS IN CHRONIC LYMPHOCYTIC LEUKEMIA

Background: An important stage in the management of patients with CLL is the prediction of the course of the disease in order to assess the need for an earlier onset of therapy and the use of alternative therapy on an individual basis, depending on the detectable prognostic markers. Aims: To determine the interrelationship of clinical-laboratory (as well as molecular-genetic) prognostic markers with various courses of CLL. Methods: We have examined 107 patients diagnosed with CLL in SI «RRC RM&HE» from 2017 to 2020. This cohort was divided into 2 groups: 1st group (49 patients) without signs of progression of CLL, and the 2nd group (58 patients) with clinical signs of disease progression after 3 years of observation. The median age in the 1st group was 61 years, in the 2nd - 62 years. The material for the study was venous blood. To determine the immunophenotype of tumor cells we used the flow cytofluorimeter FacsCanto II. Detection of β2-mg, TK and TPA was performed using the chemiluminescent analyzer. To determine the mutations of the NOTCH1 gene (34th exon), SSCP-PCR was used, followed by direct sequencing of DNA samples with conformational polymorphism. We used nonparametric statistics methods calculated in the Statistica 10.0. Statistically significant differences were considered for p<0.05. Results: Patients in group 1 differed from patients in group 2 in levels of β2-mg-1.8 and 3.5 μg/L (p<0.001) and LDH-220 and 326 U/L (p<0.002). TK levels (p<0.001) and TPA (p<0.011) were also significantly higher in group 2 (7.7 and 49.8 IU/L) compared with patients in group 1 (4.2 and 34.3 IU/L). According to immunophenotyping data, statistically significant differences were obtained on the Zap70 marker: in the 1st group the median was 10.1%, in the 2nd group - 21.6%. As a result of molecular genetic analysis, mutations in the NOTCH1 gene were identified in 14 patients. It was found that patients without progression at the time of inclusion in the study in the presence of mutations in the NOTCH1 gene had a statistically significantly shorter progression-free survival (mean 33.4 months (95% CI [22.0-44.8]) compared with patients without mutations (59.2 months (95% CI [54.1–64.3]) (p=0.018), which indicates the association of NOTCH1 mutations with a poor prognosis for disease progression in patients with CLL. Summary/Conclusion: It was found that markers such as LDH, β2-mg, TK, TPA, ZAP70 and NOTCH1 gene mutation have certain prognostic significance, which was confirmed by comparing their levels in patients with and without CLL progression after 3 years of observation. We can use NOTCH1 gene mutation as an additional factor in predicting the course of CLL. Knowledge of reliable prognostic markers may allow to initiate in-time treatment or to adjust therapy for patients with high-risk CLL with a probable increase in their life span.

A Randomized Placebo-Controlled Phase 2 Study of Metformin for the Prevention of Progression of Monoclonal Gammopathy of Undetermined Significance and Low Risk Smoldering Multiple Myeloma

Background: Multiple Myeloma (MM) is thought to evolve from the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), which are common premalignant disorders that progress to overt MM in a subset of individuals for reasons that are poorly understood. Despite increasing interest in preventing disease progression in this patient population, the standard of care still consists of close surveillance until progression to MM; however, once MM develops it cannot be cured. Therefore, the identification of prevention and interception strategies for patients with MGUS and SMM is of considerable importance.A promising pharmacologic intervention to reduce the risk of progression of MGUS/SMM to MM is metformin, a drug commonly used to treat type 2 diabetes but that is also considered safe for use in non-diabetic populations. In vivo and in vitro studies have revealed that metformin has direct antitumor effects across a variety of cancers including MM, and recent epidemiological data suggests it may reduce the risk of MM in diabetic patients with MGUS. Here, we describe the first randomized controlled trial testing the efficacy of metformin in reducing clinical signs of disease progression in patients with MGUS and SMM (NCT04850846).Study Design and Methods: This is a phase II single center, randomized controlled trial of metformin vs. placebo in patients with high-risk MGUS and low-risk SMM. The primary objective of the study is to determine whether metformin can reduce or stabilize serum monoclonal (M-)protein concentrations from baseline to 6-months. Exploratory objectives include mass spectrometry quantification of M-protein, examination of molecular evolution of tumor cells in response to metformin, as well as changes in other clinical laboratory parameters in response to metformin.To be eligible, patients must have high-risk MGUS or low-risk SMM. High-risk MGUS is defined as bone marrow plasma cell concentration <10% with one or more of the following higher-risk features: serum M-protein level ≥1.5 g/dL to <3 g/dL or abnormal free light-chain (FLC) ratio (<0.26 or>1.65); a forthcoming amendment will include non-IgG subtype as an additional high-risk feature. Low-risk SMM is defined as bone marrow plasma cells ≥10%with the absence of any features of high-risk SMM.Metformin and its corresponding placebo are the pharmacological treatments. The metformin dose is 1500 milligrams/day, provided in 500 milligram pills. To minimize gastrointestinal symptoms, metformin is started at a low dose of 500 milligram (1 pill) per day and participants gradually increase the dosage over the course of the first month of treatment until the full 1500 milligram (3 pill) per day regimen is achieved. The study treatment period is 6 months, with primary outcomes assessed at the end of the 6-month treatment period.Conclusions and Future Directions: While the cornerstone of clinical management in MGUS and SMM is to delay therapy until progression to symptomatic MM, patients and oncologists continually seek new ways to prevent end organ damage and incurable malignancy. This trial is positioned to provide preliminary but robust mechanistic data to support the development of novel prevention strategies for MGUS and SMM patients. DisclosuresMarinac: GRAIL Inc: Research Funding; JBF Legal: Consultancy. Sperling: Adaptive: Consultancy. Parnes: Sigilon: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; UniQure: Membership on an entity's Board of Directors or advisory committees; Sunovion: Consultancy; I-mAb: Consultancy; Aspa: Consultancy; Genentech/Hoffman LaRoche: Research Funding; Shire/Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Richardson: Protocol Intelligence: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Secura Bio: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy. Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure:metformin, which is an anti-diabetic medication

Drug withdrawal in patients with autoimmune hepatitis in long-term histological remission: A prospective observational study

BackgroundRecommendations for drug withdrawal in patients with autoimmune hepatitis (AIH) in longstanding remission are conflicting and rely on retrospective data. We prospectively investigated the predictive value of histological normalisation for successful treatment withdrawal in AIH patients. MethodsNon-cirrhotic patients with established AIH and complete biochemical remission (normalisation of serum alanine aminotransferase [ALT] or aspartate aminotransferase [AST] and immunoglobulin G [IgG]) of at least 2 years were biopsied. Immunosuppressive therapy was only withdrawn in patients with histological normalisation (histological activity index [HAI] ≤3) with a minimum follow-up of 12 months. ResultsA total of 17 patients in biochemical remission for at least 2 years were included. Persistent histological inflammatory activity (HAI >3) precluded drug withdrawal in five patients. These had higher values of ALT (25 vs. 16 U/L; p = 0.01) and AST (26 vs. 22 U/L; p = 0.01) compared with patients in histological remission. Immunosuppressive medication was withdrawn in 12 patients; eight (67%, C.I. 40-93% p = 0.4) remained in remission during a median follow-up of 62 months (range: 13-75 months); and four (33%, C.I. 7-60% p = 0.4) required reinstitution of therapy after 1, 6, 11, and 40 months, all without clinical signs of disease progression or hepatic decompensation. No predictors of relapse were identified. ConclusionTwo-thirds of the patients who prove to have histological normalisation after at least 2 years of biochemical remission achieve treatment-free remission. Although patient numbers were small and results should be interpreted with caution, these findings support a liver biopsy prior to drug withdrawal.

ORAL INJURIES IN A PATIENTE WITH HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION: A CASE REPORT

The first cases of Acquired Immunodeficiency Syndrome (AIDS) were reported in 1981 in patients with a high decline in immune response. Human immunodeficiency virus (HIV) infection can manifest itself through various signs and symptoms. The oral cavity is an extremely important way for diagnosis and prognosis, because oral lesions may present as clinical signs of disease progression or ineffective antiretroviral treatment. The objective of this study was to evaluate, diagnose and intervene in the oral lesions present in a patient with HIV infection. A case report study was conducted on a patient treated at the Dr. Antônio Comte Telles Polyclinic (Specialized Assistance Service for HIV / AIDS) in Manaus, Amazonas, Brazil. Lesions found in the patient were Leukemia, Smoker's Melanosis and Oral Candidiasis, the latter being treated with tongue hygiene and application of VegelipR associated with laser therapy. It was observed that the treatment was effective and in five sessions there was improvement in the lesion. Oral manifestations are closely related to the HIV virus, since they may be associated with infection and / or disease progression, indicating deficiency in the immune system, as well as interruption of antiretroviral treatment. Candidiasis is an opportunistic infection that, if properly diagnosed and treated, contributes to the improvement of the immune system. It is concluded that the knowledge of the dentist regarding the pathologies and their manifestations is important, as well as a multidisciplinary work in the reference centers for HIV. Keywords: HIV, AIDS, Oral Injury, Dentistry.

Subclinical focal cholangitis mimicking liver metastasis in asymptomatic patients with history of pancreatic ductal adenocarcinoma and biliary tree intervention

BackgroundCholangitis is an inflammatory process of the biliary tract with a wide range of clinical manifestations and it is not always considered in the differential diagnosis in asymptomatic patients. To the best of our knowledge there is no previous report in the English literature of focal cholangitis manifesting exclusively as liver parenchymal changes mimicking liver metastasis in asymptomatic patients with pancreatic ductal adenocarcinoma (PDAC) and history of manipulation of the biliary tree. The purpose of this article is to present six cases of subclinical focal cholangitis mimicking liver metastasis in asymptomatic patients with history of PDAC and biliary tree intervention.Case presentationThere are six cases with new hepatic lesions detected on follow-up scans in asymptomatic patients with history of PDAC and manipulation of biliary tree. Overall seven lesions were detected, all of them were on the liver periphery, five were hypovascular and two were hypervascular. None of those patients had elevation of CA 19.9 compared with the previous exams. The three patients that had magnetic resonance imaging presented restriction on diffusion weighted imaging and high signal intensity on T2-weighted image. Two patients underwent liver biopsy, which showed only inflammatory changes. All patients were treated with antibiotics and underwent imaging follow-up, which demonstrated resolution of the lesions. None of the patients showed imaging or clinical signs of disease progression during this interval.ConclusionRadiologists and oncologists need to be aware of the possibility of focal cholangitis causing hepatic lesions mimicking neoplasia in patients with history of biliary tree intervention, even in the absence of clinical symptoms.

Progression in Patients with with Low- and Intermediate-1 Risk Del(5q) MDS Is Predicted By a Limited Subset of Mutations

▪A high proportion of lower-risk del(5q) MDS patients will respond to treatment with lenalidomide. The estimated duration of transfusion-independence is 2 years including some long-lasting responses, but almost 40% of patients progress to acute leukemia by 5 years after start of treatment. As the molecular mechanisms underlying disease progression in del(5q) MDS remain to be elucidated, we do not know how to predict disease progression or how to monitor patients during lenalidomide treatment. We previously reported that small TP53 mutated subclones predict for an unfavorable outcome in del(5q) patients, and that these subclones expand with disease progression. However, whether or not other somatic mutations or factors related to the bone marrow microenvironment also contribute to disease progression has not been comprehensively assessed.We studied a longitudinal cohort of 35 low- and intermediate-1-risk del(5q) patients treated with lenalidomide (n=22), or other treatments including stem cell transplantation (n=13) by flow cytometric surveillance of hematopoietic stem and progenitor cells (HSPC) subsets, targeted sequencing of mutational patterns, and changes in the bone marrow microenvironment. In our cohort, 13 of 35 patients progressed to either higher-risk MDS (n=4) or leukemia (n=9), 12 of whom were treated with lenalidomide. Progression was associated with the detection of a restricted subset of new recurrent mutations, either alone or in combination: TP53 (n=9, p=0.0004), TET2 (n=6, p=0.006), RUNX1 (n=3, p=0.044), and PTPN11 (n=1). Regardless of whether the three mutations (TP53, TET2 and RUNX1) were present in the initial sample or whether they subsequently developed, testing positive for any of them carried a high probability (13/16, 81%) for predicting progression. For 11 out of 13 patients the new mutations were detected prior to the time point of clinical progression and the median time from detection of the mutation to clinical evidence of progression was 42 months (range 0-83.9). Thus, we were able to detect the mutation in the majority of cases well before clinical signs of disease progression. Seven of the nine patients who developed leukemia carried a TP53 mutation. Based on a median sequencing depth of 370 reads, the mutation was considered present pre-treatment in one of these patients and to have developed under treatment in the other six. Using flow cytometry for surveillance of HSPC subsets in lenalidomide-treated patients, we found that neither lenalidomide treatment nor the acquisition of additional mutations led to any uniform profound changes in the hematopoietic hierarchy unless the patient showed clinical signs of progression. Microarray analysis of mesenchymal stromal cells (MSC) exhibited an expression footprint consistent with MSC with high expression of typical MSC markers and absence of hematopoietic gene signatures. However, we observed only minor differences in gene expression between pre- treatment del(5q) and healthy MSC.In conclusion, while flow cytometric analysis of HSPC populations or analysis of the microenvironment had limited predictive value in this cohort of lower-risk del(5q) MDS, all patients who progressed to either higher-risk MDS or leukemia were identified by harboring recurrent mutations in a limited number of genes, i.e., TP53, RUNX1, TET2, and PTPN11. Based on our data, we advocate for conducting a prospective study aimed at investigating in a larger number of del(5q) MDS cases pre- and post-lenalidomide treatment, whether the detection of such mutations can guide clinical decision making, such as suggesting which patients should undergo hematopoietic cell transplantation. DisclosuresNo relevant conflicts of interest to declare.

Low-Burden TP53 Mutations Occur in Chronic Phase of Myeloproliferative Neoplasms Regardless of Hydroxyurea Administration, Disease Type, and JAK2 Status

▪Myeloproliferative neoplasms (MPN) are characterized by abnormal proliferation of myeloid lineages and a tendency toward leukemic transformation. Inactivation of tumor suppressor TP53 has been repeatedly associated with MPN transformation into secondary acute myeloid leukemia (sAML), but no fully expanded TP53 mutated clones in chronic phase of MPN were reported. The link between TP53 mutations and widely used cytoreductive treatment by hydroxyurea (HU) still remains controversial. To which extent TP53 mutations represent a risk of disease progression is not known. We aimed to search for low-burden TP53 mutated subclones in chronic-phase-MPN patients and to correlate presence of these clones with therapy, disease course, and other clinical features.In total we analyzed 220 patients by ultra-deep next generation sequencing (NGS). We detected TP53 mutations in 39 (18 %) patients with variant allelic frequency of 0.1-16.3 % at the first examination. The analysis of 136 patients treated with hydroxyurea or other drugs (anagrelide (ANA), interferon α (IFN)) for more than 4 years, as well as a group of 84 patients untreated by cytoreductive drugs, showed that TP53 mutations occurrence in chronic phase is independent of hydroxyurea use, disease type, and JAK2/CALR/MPL status. Mutations were found in 17/72 (24 %) HU treated patients, in 11/64 (17 %) patients treated by other drugs, and in 11/84 (13 %) untreated patients. Median size of mutated clones was 0.5 % and was not influenced by previous treatment. In 10 patients we found more than one mutation.In patients harboring TP53 mutations, retrospective samples were examined if available to explore the clonal evolution of TP53 mutated clones. The respective TP53 mutations were found in 13/20 cases analyzed; out of them, in 4 cases the mutation was found even in a diagnostic sample. Follow-up samples were examined in 28 patients with TP53 mutations and the mutation burden changed during the monitored time in majority of patients; however, the expansion into dominant clone was observed in one patient only. When all data from retrospective and prospective analyses taken together (30 patients), the median follow-up was 7.2 years. TP53 mutation burden tended to increase in 14 patients. In 6 patients the mutation burden remained stable and in 4 patients it fluctuated. In 6 patients the mutated clone size decreased; out of them in 2 originally very low-burden mutations (0.2 %) were not detectable in samples taken 15 and 3.4 years later. We did not observe any correlations of different patterns in TP53 mutation changes with therapy or other clinical characteristics (disease type, driver mutation, time from diagnosis, treatment response).Further, we assessed the TP53 mutation impact on overall survival and leukemic transformation. The mutations did not negatively affect disease progression or overall survival either from diagnosis or from mutation identification. sAML developed in 2 patients with TP53 mutations 17.9 (treated with IFN) and 8.3 (treated with HU) years from diagnosis. In the latter patient, the sAML developed from a different clone as it was TP53-wt, JAK2-wt, although 2 TP53 mutated clones within JAK2 mutated clone were detected in chronic phase. On the other hand, we have observed another interesting case where the TP53 mutation burden grew rapidly from 10 % up to nearly 100 % during the follow-up. In contrast to published data, this patient did not show any clinical signs of disease progression for 2 years after the expansion and died of MPN unrelated cause.In summary, using highly sensitive method we showed that low-burden TP53 mutations are present in MPN chronic phase. Neither their presence nor their size is associated with previous therapy and has impact on overall survival or leukemic transformation. Monitoring of TP53 mutations during the disease course showed that their clonal development is rather variable; nevertheless, TP53 minor mutations may represent a pool for future clonal evolution.Supported by MZ CR-RVO (FNBr, 65269705), MUNI/A/1028/2015, H2020 692298, MZO AZV 15-31834A, 15-30015A, MEYS LQ1601 and LM2015064. DisclosuresGisslinger:Baxalta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan: Consultancy, Honoraria. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees.

Pseudomyxoma peritonei, a rare tumors of the abdomen: Palliative treatment and response to low-dose capecitabine and/or bevacizumab

Pseudomyxomaperitonei is a rare abdominal tumor originating from epithelial appendiceal cancer. Its incidence is estimated at 1 per million per year. In this chapter, we present case reports of two separate patients treated with palliative intent with low-dose capecitabine daily ± bevacizumab and therapy beginning after clear radiological and clinical signs of disease progression. During the period of palliative low-dose capecitabine treatment, both patients had at least a two-year period of stabilized disease and progression-free interval with an outstanding quality of life. Low-dose capecitabine and/or bevacizumab may be beneficial in the palliative treatment of pseudomyxoma peritonei.

QOL-22THE IMPACT OF PREGNANCY ON GLIOMA PATIENTS

OBJECTIVE: To describe outcomes of glioma patients who become pregnant. BACKGROUND: Few data exist regarding the effect of pregnancy on gliomas, making it challenging to counsel glioma patients of reproductive age regarding potential risks. Individual case reports and small series report increased rates of tumor progression with pregnancy. METHODS: This was an IRB-approved retrospective study of women with gliomas who became pregnant during their disease course or were diagnosed with gliomas during the peripartum period defined as during pregnancy or the 12 months following delivery. Outcomes analyzed included radiographic and clinical signs of disease progression. RESULTS: We identified 82 patients: 38 with known gliomas who became pregnant, 27 diagnosed with gliomas during pregnancy, and 17 diagnosed with gliomas in the postpartum period. Histologies included astrocytoma(33%), oligodendroglioma(33%), mixed oligoastrocytoma(21%), and other gliomas(5%); pathology was unavailable for 7 patients. The majority of patients had WHO II tumors(56%), followed by WHO III(30%), WHO I(2%), and WHO IV(2%). The most common presenting symptom of glioma was seizure(55%). Four patients underwent surgical resection during pregnancy. No patient received radiation or temozolomide during pregnancy. There were 85 pregnancies examined. There were 20 known Cesarean sections and 4 elective terminations. Of the 36 patients with known gliomas who carried a pregnancy to delivery, 10 had radiographic progression during the peripartum period. Ten patients experienced recurrent neurological symptoms during pregnancy including seizures, headache, and hemorrhage into a pituitary adenoma. All babies were healthy. CONCLUSIONS: A noticeable number of women harboring a glioma were diagnosed in the peripartum period suggesting that pregnancy is a potential stimulant of tumor growth. For women with known gliomas, 28% developed radiographic progression during pregnancy. Women of reproductive age with gliomas should be counseled on the potential impact of pregnancy on tumor growth, however, the majority of pregnancies in glioma patients were uncomplicated.

Radiological and clinical results following high-dose intensity-modulated radiotherapy in recurrent craniopharyngioma: A case report.

Craniopharyngiomas (CPs) are rare benign suprasellar tumors. The standard treatment for CP is complete surgical resection or partial resection followed by adjuvant radiotherapy (RT). Adjuvant RT is typically administered at a total dose of 54 Gy with 1.8 Gy/fraction. The current study reported the case of a young patient affected by recurrent craniopharyngioma, who was treated with irradiation subsequent to several surgical resections. Image fusion and intensity-modulated radiation therapy techniques were employed to deliver a high total dose (63 Gy with 2.1 Gy/fraction) with no severe acute toxicities recorded. At the 6-year follow-up, no radiological or clinical signs of disease progression or late sequelae were observed.

PROGNOSTIC FACTORS OF NON-HODGKIN LYMPHOMA: RETROSPECTIVE STUDY IN UNIT BLOOD SERVICE OF THE INTERNAL MEDICINE DANTEC IN DAKAR (SENEGAL)

INTRODUCTION: The non-Hodgkin's lymphoma is the monoclonal proliferation of B and T lymphocyte cells, responsible for the development of tumors in lymphoid organs. The objective of this study was to describe the prognostic factors for NHL and their impact in the care of patients METHODOLOGY: This is a descriptive retrospective study on patients hospitalized files Medical Clinic I of the Aristide Le Dantec Hospital from January 2005 to December 2009. Were included in the study, patients for whom diagnosis of non-Hodgkin lymphoma was made on the basis of the results of histological and / or immuno-phenotypic examination of the biopsy specimen. Prognostic factors were studied and classified according to the prognostic scores in order to assess their impact on patient survival. Data analysis was done thanks to the IPSS software and the significance level was set at p ≤ 5%. RESULTS: NHL 44 cases represented on all patients hospitalized for haematological malignancies during this period, a prevalence of 45.4%. We have noted an increase in the incidence of NHL 2005 to 2009. The sex ratio was 2.6 / 1 and the mean age was 46.77 years [17-78 years]. Among the general symptoms, fever and weight loss were in the forefront (61.4% of patients) and lymph nodes were the most frequent physical signs (75%) followed by splenomegaly (47.7%). anemia was found in 72.7% of cases, leukocytosis in 45.5% of cases and thrombocytopenia in 47.7% of patients. Thirty-seven point four percent of patients were classified stage IV Ann Arbor at diagnosis. The presence of general signs scalability B was observed in 70% of patients. Regarding the prognostic factors, the International Prognostic Index (IPI) was studied in 43.2% of patients (n = 19) patients showed that 16% (n = 3) were IPI 1; 37% (n = 7) had an intermediate risk (IPI 3 and 4) and the remaining 10% were high risk (IPI 4). The IPI adjusted for age (aaIPI), noted a correlation of the IPI with certain age groups (50 and 60 years, p = 0.00001, 60 and 70, p = 0.00001). All patients were classified LLC Binet stage C and FLIPI was low (1-2). Evolution were marked by a 100% survival for low-risk patients (with a statistically significant correlation between survival and IPI 1: p <0.00001) and a death rate of 100% for high-risk patients (p <0.00001). The evolution was marked by a prolonged clinical and laboratory remission in 61.3% of cases, 11.4% of patients lost to 27.4% of deceased patients. CONCLUSION: Poor prognostic factors for lymphomas are mainly represented by the advanced Ann Arbor, international prognostic index (IPI) high and the presence of clinical signs of disease progression of the dice inclusion.

Metallic gold beads in hyaluronic acid: a novel form of gold-based immunosuppression? Investigations of the immunosuppressive effects of metallic gold on cultured J774 macrophages and on neuronal gene expression in experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a neurodegenerative disease caused by recurring attacks of neuroinflammation leading to neuronal death. Immune-suppressing gold salts are used for treating connective tissue diseases; however, side effects occur from systemic spread of gold ions. This is limited by exploiting macrophage-induced liberation of gold ions (dissolucytosis) from gold surfaces. Injecting gold beads in hyaluronic acid (HA) as a vehicle into the cavities of the brain can delay clinical signs of disease progression in the MS model, experimental autoimmune encephalitis (EAE). This study investigates the anti-inflammatory properties of metallic gold/HA on the gene expression of tumor necrosis factor (Tnf-α), Interleukin (Il)-1β, Il-6, Il-10, Colony-stimulating factor (Csf)-v2, Metallothionein (Mt)-1/2, Bcl-2 associated X protein (Bax) and B cell lymphoma (Bcl)-2 in cultured J774 macrophages and in rodents with early stages of EAE. Cells grew for 5 days on gold/HA or HA, then receiving 1,000 ng/mL lipopolysaccharide (LPS) as inflammatory challenge. In the EAE experiment, 12 Lewis rats received gold injections and control groups included 11 untreated and 12 HA-treated EAE rats and five healthy animals. The experiment terminated day 9 when the first ten animals showed signs of EAE, only one of which were gold-treated (1p = 0.0367). Gene expression in the macrophages showed a statistically significant decrease in Il-6, Il-1β and Il-10-response to LPS; interestingly HA induced a statistically significant increase of Il-10. In the EAE model gene expression of inflammatory cytokines increased markedly. Compared to EAE controls levels of Tnf-α, Il-1β, Il-10, Il-6, IL-2, Ifn-γ, Il-17, transforming growth factor (Tgf)-β, superoxide dismutase (Sod)-2, Mt-2 and fibroblast growth factor (Fgf)-2 were lower in the gold-treated group. HA-treated animals expressed similar or intermediate levels. Omnibus testing for reduced inflammatory response following gold-treatment was not significant, but tendencies towards a decrease in the Sod-2, Fgf-2, Il-1β response and a higher Bdnf and IL-23 gene expression were seen. In conclusion, our findings support that bio-liberation of gold from metallic gold surfaces have anti-inflammatory properties similar to classic gold compounds, warranting further studies into the pharmacological potential of this novel gold-treatment and the possible synergistic effects of hyaluronic acid.

Role of PET/CT in the Diagnostic Work-up of Patients with Chronic Lymphocytic Leukemia (CLL) and Clinical Signs of Disease Progression

AbstractAbstract 3888Chronic lymphocytic leukemia (CLL) is a heterogeneous leukemia with a very variable outcome. The occurrence of a second malignancy (SM) or of a disease transformation (DT) may complicate the course of the disease. An aggressive diffuse large B-cell lymphoma (DLBCL) and, less frequently, a Hodgkin’s lymphoma (HL) are the most commonly observed forms of DT, defined as Richter’s syndrome (RS). Since the presence of enlarged “bulky nodes”, as well as the observation of extra-nodal lesions, can lead both to the suspicion of a CLL progression and to the possibility of a DT or of a SM, a biopsy of the involved tissue is the only appropriate approach for a correct diagnosis. Positron emission tomography/computed tomography (PET/CT) is currently used for the initial staging and restaging of HL and DLBCL, as well as for the identification of other malignancies. In a previous report by Bruzzi et al. (JNM, 2006), PET/CT showed a high predictive value in demonstrating or excluding DT. The same finding has been observed in single case reports, where in patients with CLL a high 18F-FDG uptake was associated with the presence of a DLBCL. With the aim of discriminating the presence of a DT or a SM malignancy, between June 2008 and June 2012, a PET/CT exam followed by the biopsy of the involved tissue was performed in CLL patients from 4 Italian centers. Patients included in this study showed disease progression requiring treatment according to the 2008 revised IWCLL criteria and clinical signs suggestive of the presence of a more aggressive disease, such as rapidly enlarging or bulky lymph nodes (diameter ≥5 cm) and/or extra-nodal lesions associated with at least one additional sign including B systemic symptoms, increased serum lactate dehydrogenase (LDH), increased β2 microglobulin (B2M). The 18F-FDG uptake was correlated with the histologic findings and, for the purpose of this study, a maximum standardized uptake value (SUVmax) ≥5 was considered highly suggestive of a more aggressive disease. Data on 64 CLL patients (median age, 66 years, range, 35–85) were retrospectively analyzed. At the time of PET/CT, the median follow-up from CLL diagnosis was 73 months (range, 3– 227 months) and a Binet C stage was observed in 16 cases (25%). Twenty-three (36%) patients were treatment-naïve and 41 (64%) had been previously treated (median number of prior treatments, 2; range, 1–4), including 14 (22%) refractory cases. Systemic symptoms were recorded in 25% of cases, LDH was increased in 41% and B2M in 72%. The majority of patients (61%) were IGVH unmutated, 45% CD38 positive and 56% ZAP-70 positive. Bulky lymph nodes (diameter ≥5 cm) and/or marked splenomegaly (longitudinal diameter ≥17 cm) were observed in 30 cases (47%). Evidence of extra-nodal disease was recorded in 8 cases (12.5%): thyroid, 2 cases; uterine fundus, 1; gastric,1; bone, 1; nasopharynx, 1; skin infiltrates, 2. The biopsy confirmed a SLL/CLL diagnosis in 44 cases, a DT in 15 (DLBCL, 10; HL, 5) and SM in 5 (thyroid cancer + SLL/CLL, 2 cases; lymph node metastasis of carcynoid + SLL/CLL, 1; lymph-node metastasis of a squamous cancer, 1; lejomioma of the uterine fundus,1). Sites of abnormal 18F-FDG uptake having a SUVmax ≥5 were recorded in a total number of 30 cases, in 13/44 cases (30%) with a SLL/CLL histology, in 13/15 with DT (87%), including 9/10 (90%) cases of DLBCL and 4/5 (80%) HL. An abnormal uptake was recorded also in 4/5 patients with SM. Based on these results, for the diagnosis of a DT or SM, PET/CTPET/CT showed an overall sensitivity, specificity, positive and negative predictive values of 85% 70%, 57% and 91%, respectively, while for the diagnosis of a DT (DLBCL+HL) the sensitivity, specificity, positive and negative predictive values were 87%, 65%, 43% and 94%, respectively. The cases with a SLL/CLL histology having a SUVmax ≥5 were characterized by a higher Ki-67% expression (p=0.0001) suggesting a high rate of cell turnover. Our results show that a PET/CT performed in CLL patients at the time of disease progression can detect cases with a high likelihood of DT or SM, representing therefore a very helpful imaging technique in guiding the appropriate site that should be considered for biopsy. Disclosures:No relevant conflicts of interest to declare.

Metallic gold slows disease progression, reduces cell death and induces astrogliosis while simultaneously increasing stem cell responses in an EAE rat model of multiple sclerosis

Multiple sclerosis (MS) is the most common neurodegenerative disease in the Western world affecting younger, otherwise healthy individuals. Today no curative treatment exists. Patients suffer from recurring attacks caused by demyelination and underlying neuroinflammation, ultimately leading to loss of neurons. Recent research shows that bio-liberation of gold ions from metallic gold implants can ameliorate inflammation, reduce apoptosis and promote proliferation of neuronal stem cells (NSCs) in a mouse model of focal brain injury. Based on these findings, the present study investigates whether metallic gold implants affect the clinical signs of disease progression and the pathological findings in experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. Gold particles 20-45μm suspended in hyaluronic acid were bilaterally injected into the lateral ventricles (LV) of young Lewis rats prior to EAE induction. Comparing gold-treated animals to untreated and vehicle-treated ones, a statistically significant slowing of disease progression in terms of reduced weight loss was seen. Despite massive inflammatory infiltration, terminal deoxynucleotidyl transferase dUTP nick end labeling staining revealed reduced apoptotic cell death in disease foci in the brain stem of gold-treated animals, alongside an up-regulation of glial fibrillary acidic protein-positive reactive astrocytes near the LV and in the brain stem. Cell counting of frizzled-9 and nestin-stained cells showed statistically significant up-regulation of NSCs migrating from the subventricular zone. Additionally, the neuroprotective proteins Metallothionein-1 and -2 were up-regulated in the corpus callosum. In conclusion, this study is the first to show that the presence of small gold implants affect disease progression in a rat model of MS, increasing the neurogenic response and reducing the loss of cells in disease foci. Gold implants might thus improve clinical outcome for MS patients and further research into the long-term effects of such localized gold treatment is warranted.

Role of serum S100B and PET-CT in follow-up of patients with cutaneous melanoma

BackgroundIncreased level of serum S100B can serve as a marker of metastatic spread in patients with cutaneous melanoma (CM). In patients with elevated S100 B and/or clinical signs of disease progression PET-CT scan is a valuable tool for discovering metastases and planning treatment.The aims of this study were to determine whether regular measurements of serum S100B are a useful tool for discovering patients with CM metastases and to evaluate the diagnostic value of PET-CT during the follow-up.MethodsFrom September 2007 to February 2010, 115 CM patients included in regular follow up at the Institute of Oncology Ljubljana were appointed to PET-CT. There were 82 (71.3%) patients with clinical signs of disease progression and 33 (28.7%) asymptomatic patients with two subsequent elevated values of S100B. Sensitivity, specificity, positive and negative predictive value (PPV, NPV) of S100B and PET-CT were calculated using standard procedures.ResultsDisease progression was confirmed in 81.7% of patients (in 86.5% of patients with clinical signs of disease progression and in 69.7% of asymptomatic patients with elevated S100B). Sensitivity, specificity, PPV and NPV of S100B was 33.8%, 90.9%, 96.0% and 17.5% in patients with clinical signs of disease progression. In 20.0% of patients increased serum S100B was the only sign of disease progression. Sensitivity and PPV of S100 in this group of patients were 100.0% and 69.7%.With PET-CT disease progression was diagnosed in 84.2% of symptomatic patients and in 72.7% of asymptomatic patients with elevated S100B. The sensitivity, specificity, PPV and NPV of PET-CT for symptomatic patients was 98.5%, 90.9%, 98.5% and 90.9% and 100%, 90.0%, 95.8% and 100% for asymptomatic patients with elevated S100.ConclusionsMeasurements of serum S100B during regular follow-up of patients with CM are a useful tool for discovering disease progression in asymptomatic patients. The value of its use increases if measurements are followed by extended whole body PET-CT.

Risk factors for and management of cognitive dysfunction in multiple sclerosis

Cognitive impairment is common in multiple sclerosis (MS), especially when assessed by neuropsychological tests that emphasize mental processing speed, episodic memory, and some aspects of executive function. In this Review, we question why some MS patients develop severe impairment in cognitive abilities, while cognitive ability remains intact in others. We find that the heterogeneity in neuropsychological presentation among patients with MS reflects the influence of many factors, including genetics, sex, intelligence, disease course, comorbid neuropsychiatric illness, and health behaviors. Neuropsychological deficits are also robustly correlated with brain MRI metrics. Male patients with early evidence of cerebral gray matter atrophy are most prone to impairment, whereas high premorbid intelligence improves the neuropsychological prognosis. Routine evaluation of cognition is useful for helping patients to navigate problems related to activities of daily living and work disability and, if reliable methods are employed, cognitive decline can be detected and included among the many clinical signs of disease progression or treatment failure. Pharmacological treatments for neuropsychological impairment are on the horizon, although presently no firm medical indications exist for the condition.

Lenalidomide as Single Agent to Control Minimal Residual Disease in Chronic Lymphocytic Leukemia In First Complete Remission: Report of Three cases

AbstractAbstract 4640 Introduction.Lenalidomide is a novel therapeutic agent with immunomodulatory activity, that is clinically active in myelodysplastic syndrome and multiple myeloma. Recent clinical trials have shown that Lenalidomide may have clinical efficacy also in patients with Chronic Lymphocytic Leukemia (CLL). Studies so far reported have been carried out in patients with refractory or relapsed CLL. Besides its clinical efficacy, some concerns have been raised on the possible toxicity of Lenalidomide, with some unique effects, namely tumor flare reactions and tumor lysis syndrome, observed in CLL patients. A recent pilot study has been started at our Institution aimed to verify safety and efficacy of Lenalidomide given to control persistent minimal residual disease (MRD) in patients with CLL in 1st Complete Remission (CR). The selection of patients in 1st CR had a dual advantage: i. the possible use of Lenalidomide as single agent, without any other concurrent chemo-immunotherapeutic drugs that might interact in the clinical response; ii. the presence of low tumor burden, that allows to minimize the risk of severe side effects, in particular the risk of tumor lysis syndrome. So far, three patients have concluded the first year of Lenalidomide. Their clinical outcome, including treatment feasibility and monitoring of MRD, is here reported. Patients and treatment plans.Case # 1: male, aged 53 yrs. in 2002 when he had a diagnosis of B-CLL, with mutated IgH genes; he remained in watchful waiting (w/w) for two yrs., then he received a Fludarabine-based treatment supplemented with Rituximab, achieving CR in September 2005; he then received 2-yr. maintenance with Rituximab; since 2008 he was off-therapy in clinical CR; Case # 2: male, aged 59 yrs. in 2005 when he had a diagnosis of B-CLL, with mutated IgH genes; he remained in w/w for three yrs., then he received a Fludarabine-based treatment supplemented with Rituximab, achieving CR in May 2008; thereafter he was off-therapy in clinical CR; Case # 3: female, aged 38 yrs. in 2002 when she had a diagnosis of B-CLL, with un-mutated IgH genes and she received an induction treatment with Fludarabine supplemented with Rituximab, achieving CR in April 2003; she then received prolonged and intermittent maintenance treatments with Rituximab; since 2008 she was off-therapy in clinical CR. All these patients showed a slow though continuous increase of their clonal B-cell population, identified by cytofluorimetric analysis as CD19+/CD5+ve cells. Based on the increase of the MRD, the patients were placed under Lenalidomide, given at 15 mg/day for 3 weeks/month, until disease progression or discontinuation for severe toxicity. Aspirin at 100 mg. daily was added for thromboembolic prophylaxis. Lenalidomide administration was approved by the Italian National Agency of drugs (AIFA). Results.Presently, all three patients are under Lenalidomide since 12 consecutive months, according to the planned treatment. There have been no severe toxicities, in particular neither tumor flare nor symptoms related to tumor lysis have been recorded. So far, no patients showed clinical signs of disease progression. MRD has been carefully monitored by immunophenotypic analysis on both bone marrow and peripheral blood. In details, the CD19+/CD5+ve clonal B-cell population progressively decreased under Lenalidomide in two patients, with the following changes over 1 yr. before and 1 yr. after Lenalidomide, respectively: 5 to 66 cells/μ L before, then reduction to 12 cells/μ L, in case #1; 189 to 4,480 cells/μ L before, then reduction to 1,317 cells/μ L, in case #2; the clonal B-cell population is still growing (from 67 to 116 cells/μ L before, and then up to 497/μ L after Lenalidomide) in the third patient, with un-mutated B-CLL. A significant increase of the activated T-cell (CD3+/DR+) population has been observed in all three patients following Lenalidomide. Conclusions.This pilot study suggests that: i. Lenalidomide can be administered at 15 mg/day, 21 days/month, for over 1 yr. to patients with B-CLL in first CR, with reduced risks of severe side effects; ii. this schedule may be effective to control the expansion of the MRD in patients with B-CLL in clinical CR; iii. further studies on large series should be planned to verify in which patient subsets Lenalidomide might be offered, in order to reduce or even eliminate the MRD that usually persists in B-CLL patients following induction chemo-immunotherapy. Disclosures:Off Label Use: Lenalidomide in CLL in first CR to control MRD.

Does isochromosome 7q mandate bone marrow transplant in children with Shwachman-Diamond syndrome?

We report on nine children with Shwachman-Diamond syndrome (SDS), eight of whom had clonal abnormalities of chromosome 7. Seven children had an isochromosome 7 [i(7)(q10)] and one a derivative chromosome 7, all with an apparently identical (centromeric) breakpoint. Children with SDS are predisposed to myelodysplasia (MDS) and acute myeloid leukaemia (AML) often with chromosome 7 abnormalities. Allogeneic transplants have been used to treat these children, however, they are a high-risk transplant group and require careful evaluation. Three of the children were transplanted but only one survived, who to our knowledge remains the longest surviving SDS transplant patient (4.5 years +). The six non-transplanted children are well. In classic MDS, chromosome 7 abnormalities are associated with rapid progression to acute leukaemia; however, we present evidence to suggest that isochromosome 7q may represent a separate disease entity in SDS children. This is a particularly interesting finding given that the SDS gene has recently been mapped to the centromeric region of chromosome 7. Our studies indicate that i(7)(q10) is a relatively benign rearrangement and that it is not advisable to offer allogeneic transplants to SDS children with i(7)(q10) alone in the absence of other clinical signs of disease progression.