Investigation of a healthcare-associated Candida tropicalis candidiasis cluster in a haematology unit and a systematic review of nosocomial outbreaks.

BACKGROUND: Non-albicans Candida spp. are an emerging cause of hospital-acquired bloodstream infections, associated with high mortality due to the challenges in diagnosis and delayed treatment. OBJECTIVES: We aimed to investigate a cluster of healthcare-associated invasive candidiasis caused by C tropicalis and review the literature of healthcare-associated outbreaks or clusters caused by C tropicalis. METHODS: An investigation was performed to determine clinical presentation, treatment outcomes and the factors contributing to C tropicalis candidemia occurrence. We searched the Medline database via PubMed and Ovid using the keywords of "Candida tropicalis" combined with "outbreak" or "clustering" or "clusters," and we limited the search to studies conducted from January 1989 to January 2019. RESULTS: We report two related cases of C tropicalis candidemia among patients with AML following a period of neutropenia, who had erythematous skin rash as a first manifesting sign of candidiasis. C tropicalis was isolated from blood and skin cultures of both patients, which were identical by pulsed-field gel electrophoresis typing. Our systematic review of outbreaks caused by C tropicalis suggests that (a) most reported outbreaks have occurred in neonatal and adult ICUs; (b) patients who receive total parenteral therapy, antibiotics and those who have indwelling catheters and recent surgery are at high risk of infection; and (c) environmental and healthcare personnel surveillance suggest that cross-contamination is a major risk factor. CONCLUSION: Control of nosocomial outbreaks caused by C tropicalis should include better infection control measures, education of healthcare professionals especially working in adult and neonatal intensive care and haematology units.

Somatic mutations of isocitrate dehydrogenases 1 and 2 are prognostic and follow-up markers in patients with acute myeloid leukaemia with normal karyotype.

BACKGROUND: Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes are frequent molecular lesions in acute myeloid leukaemia with normal karyotype (AML-NK). The effects of IDH mutations on clinical features and treatment outcome in AML-NK have been widely investigated, but only a few studies monitored these mutations during follow-up. PATIENTS AND METHODS: In our study samples from 110 adult de novo AML-NK were studied for the presence of IDH1 and IDH2 mutations, their associations with other prognostic markers and disease outcome. We also analyzed the stability of these mutations during the course of the disease in complete remission (CR) and relapse. RESULTS: IDH mutations were found in 25 (23%) patients. IDH+ patients tend to have lower CR rate compared to IDH-patients (44% vs 62.2%, p = 0.152), and had slightly lower disease free survival (12 months vs 17 months; p = 0.091). On the other hand, the presence of IDH mutations had significant impact on overall survival (2 vs 7 months; p = 0.039). The stability of IDH mutations were studied sequentially in 19 IDH+ patients. All of them lost the mutation in CR, and the same IDH mutations were detected in relapsed samples. CONCLUSIONS: Our study shows that the presence of IDH mutations confer an adverse effect in AML-NK patients, which in combination with other molecular markers can lead to an improved risk stratification and better treatment. Also, IDH mutations are very stable during the course of the disease and can be potentially used as markers for minimal residual disease detection.

Appearance of estrogen positive bilateral breast carcinoma with HER2 gene amplification in a patient with aplastic anemia.

Immunosuppressive therapy is one of the standard therapy protocols for aplastic anemia (AA). However, immunosuppressive therapy and androgenic steroids can promote development of solid tumors such as squamous carcinoma, head and neck tumors, adenocarcinoma of the stomach, hepatocarcinoma and breast carcinoma in long surviving patients with aplastic anemia. We present here a rare case of a 56-year-old woman in whom bilateral adenocarcinoma of the breast developed 11 years after the start of immunosuppressive and androgenic steroid therapy for aplastic anemia. Histological examination showed invasive ductal carcinoma with intense nuclear staining for estrogen receptors. Her2 immunohistochemistry was positive for 80% of stained cells, and chromogenic in situ hybridization showed a high level of HER2 gene amplification. This case indicated that a new therapy option is needed for estimation and evaluation to avoid the consequence of cancer occurrence.

Disseminated cerebral cryptococcosis after silent West Nile virus infection in a patient with polycythemia vera: A case report and review of the literature.

Although disseminated cryptococcosis can occur occasionally, it is most commonly seen in immunodeficient patients. In 2005, a 43-year-old man was diagnosed with polycythemia vera. Following in 2018, he experienced an unknown-cause fever and headache. To establish the source of the symptoms, a magnetic resonance imaging scan of the brain was performed, which indicated meningeal and gyral-leptomeningeal thickening and several localized T2 hyperintense lesions measuring up to 10 × 14 mm in diameter. Cryptococcus neoformans was then cultivated from cerebrospinal fluid. Serum IgM antibodies against West Nile Virus were positive. After 8 weeks of treatment with amphotericin B and fluconazole, the overall condition improved, and the cerebrospinal fluid control culture became negative. The symptoms returned shortly after discontinuing antifungal therapy, necessitating the reintroduction of fluconazole. Currently, the patient is stable and responding positively to ruxolitinib. Here, it is demonstrated how a patient with polycythemia vera due to immunological weakness might develop disseminated cryptococcosis of the brain after West Nile virus infection.

Molnupiravir compared to nirmatrelvir/ritonavir for COVID-19 in high-risk patients with haematological malignancy in Europe. A matched-paired analysis from the EPICOVIDEHA registry.

INTRODUCTION: Molnupiravir and nirmatrelvir/ritonavir are antivirals used to prevent progression to severe SARS-CoV-2 infections and decrease hospitalisation and mortality rates. Nirmatrelvir/ritonavir was authorised in Europe in December 2021, whereas molnupiravir is not yet licensed in Europe as of February 2022. Molnupiravir may be an alternative to nirmatrelvir/ritonavir because it is associated with fewer drug-drug interactions and contraindications. A caveat for molnupiravir is the mode of action induces viral mutations. Mortality rate reduction with molnupiravir was less pronounced than that with nirmatrelvir/ritonavir in patients without haematological malignancy. Little is known about the comparative efficacy of the two drugs in patients with haematological malignancy at high-risk of severe COVID-19. Thus, molnupiravir and nirmatrelvir/ritonavir were compared in a cohort of patients with haematological malignancies. METHODS: Clinical data from patients treated with molnupiravir or nirmatrelvir/ritonavir monotherapy for COVID-19 were retrieved from the EPICOVIDEHA registry. Patients treated with molnupiravir were matched by sex, age (±10 years), and severity of baseline haematological malignancy to controls treated with nirmatrelvir/ritonavir. RESULTS: A total of 116 patients receiving molnupiravir for the clinical management of COVID-19 were matched to an equal number of controls receiving nirmatrelvir/ritonavir. In each of the groups, 68 (59%) patients were male; with a median age of 64 years (interquartile range [IQR] 53-74) for molnupiravir recipients and 64 years (IQR 54-73) for nirmatrelvir/ritonavir recipients; 56.9% (n=66) of the patients had controlled baseline haematological malignancy, 12.9% (n=15) had stable disease, and 30.2% (n=35) had active disease at COVID-19 onset in each group. During COVID-19 infection, one third of patients from each group were admitted to hospital. Although a similar proportion of patients in the two groups were vaccinated (molnupiravir n=77, 66% vs. nirmatrelvir/ritonavir n=87, 75%), more of those treated with nirmatrelvir/ritonavir had received four vaccine doses (n=27, 23%) compared with those treated with molnupiravir (n=5, 4%) (P<0.001). No differences were detected in COVID-19 severity (P=0.39) or hospitalisation (P=1.0). No statistically significant differences were identified in overall mortality rate (P=0.78) or survival probability (d30 P=0.19, d60 P=0.67, d90 P=0.68, last day of follow up P=0.68). Deaths were either attributed to COVID-19, or the infection was judged by the treating physician to have contributed to death. CONCLUSIONS: Hospitalisation and mortality rates with molnupiravir were comparable to those with nirmatrelvir/ritonavir in high-risk patients with haematological malignancies and COVID-19. Molnupiravir is a plausible alternative to nirmatrelvir/ritonavir for COVID-19 treatment in patients with haematological malignancy.

Nirmatrelvir/ritonavir in COVID-19 patients with haematological malignancies: a report from the EPICOVIDEHA registry.

Background: Nirmatrelvir/ritonavir treatment decreases the hospitalisation rate in immunocompetent patients with COVID-19, but data on efficacy in patients with haematological malignancy are scarce. Here, we describe the outcome of nirmatrelvir/ritonavir treatment in a large cohort of the latter patients. Methods: This is a retrospective cohort study from the multicentre EPICOVIDEHA registry (NCT04733729) on patients with haematological malignancy, who were diagnosed with COVID-19 between January and September 2022. Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan-Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir. Findings: A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448-4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619-8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093-0.732) and obesity (aOR 0.105, 95%CI 0.014-0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p = 0.036). No factor was observed explaining the mortality difference in patients after nirmatrelvir/ritonavir administration. Interpretation: Haematological malignancy patients were more likely to receive nirmatrelvir/ritonavir when reporting extrapulmonary symptoms or 2nd vaccine booster at COVID-19 onset, as opposed to chronic pulmonary disease and obesity. The mortality rate in patients treated with nirmatrelvir/ritonavir was lower than in patients with targeted drugs other than nirmatrelvir/ritonavir. Funding: EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223).

Induction chemotherapy versus palliative treatment for acute myeloid leukemia in a consecutive cohort of elderly patients.

A retrospective survey of 210 consecutive patients aged ≥ 65 years (median age 69 years, range 65-88 years) with acute myeloid leukemia (AML) diagnosed at a single center over a 6-year period (January 2001 to December 2006) is presented. De novo AML was diagnosed in 179 (85.2 %) patients and 31 (14.7 %) patients had a secondary AML. Twenty-three patients had M0 (11 %), 36 M1 (17.15 %), 57 M2 (27.1 %), eight M3 (3.8 %), 45 M4 (21.4 %), 31 M5 (14.8 %), one M6 (0.5 %), one M7 (0.5 %), and eight patients had unclassified myeloid leukemia (3.8 %) according to French-American-British (FAB) Study Group Classification. Eight patients with M3 (acute promyelocytic leukemia) were excluded from the study. Cytogenetic analysis was performed in 172/202 (85 %) patients. The normal karyotype was found in 81/172 (47 %), high risk aberrations in 32/172 (18.6 %), and favorable karyotype in 13/172 (7.5 %) patients. Supportive and palliative therapies were applied in 115 (56.9 %) patients, a no induction chemotherapy (NIC) group, and 87 (43.1 %) patients received induction chemotherapy (IC group). Complete remission (CR) was achieved in 45/87 (51.7 %) in the IC group and in 5/115 (4.3 %) in the NIC group of patients. After a median follow up of 4 years, 194 (96 %) patients died. The variables significantly associated with a longer overall survival (OS) by univariate analysis were an age of <75 years, a better ECOG performance status (PS) (p = 0.000, CI 95.0 %, 1.358-2.049), a serum LDH activity <600 U/l (p = 0.000, CI 95.0 %, 1.465-2.946), lower white blood cell (WBC) count at diagnosis (p = 0.011, CI 95.0 %, 1.102-2.100), lower comorbidity HCT-CI index (p = 0.000, CI 95 % 2.209-3.458), absence of splenomegaly (p = 0.015, CI 95.0 %, 1.082-2.102) and hepatomegaly (p = 0.008, CI 95.0 %, 1.125-2.171), and no preceding nonhematological malignancy. Multivariate analysis showed that significant factors affecting OS in the IC group were achievement of CR (p = 0.000), the ECOG PS (p = 0.045) and the ECOG PS (p = 0.000), and HCT-CI (p = 0.000) in the NIC group of elderly patients. The present study suggests that a subgroup of elderly patients with both ECOG PS and HCT-CI ≤ 2 at presentation may be eligible for intensive induction chemotherapy.

Prognostic impact of NPM1 mutations in Serbian adult patients with acute myeloid leukemia.

Based on current findings, the presence of NPM1 mutations in acute myeloid leukemia (AML) patients is associated with an increased probability of complete remission (CR) and better overall survival (OS). We determined the incidence and prognostic relevance of NPM1 mutations, their association with FLT3 and IDH mutations, and other clinical characteristics in Serbian adult AML patients. Samples from 111 adult de novo AML patients, including 73 AML cases with a normal karyotype (NK-AML), were studied. NPM1, FLT3, and IDH mutations were detected by PCR and direct sequencing. NPM1 mutations were detected in 22.5% of patients. The presence of NPM1 mutations predicted a low CR rate and shorter OS. NPM1 mutations showed an association with both FLT3 and IDH mutations. Survival analysis based on NPM1/FLT3 mutational status revealed a lower OS for NPM1(+)/FLT3(-) compared to the NPM1(-)/FLT3(-) group in NK-AML patients. The lack of impact or unfavorable prognostic effect of NPM1 mutations found in this study can be assigned to a small cohort of analyzed AML patients, as can the presence of FLT3 and IDH mutations or other genetic lesions that cooperate with NPM1 mutations influencing prognosis.

Alveolar granulocytic sarcoma of the mandible in a patient with HIV.

BACKGROUND: Granulocytic sarcoma (chloroma) occurs primarily in patients with acute myelogenous leukemia although it can also appear in connection with other myeloproliferative disorders. CASE REPORT: We present the case of a 52-year-old human immunodeficiency virus (HIV)-positive female patient with a CD4+ count of 321 cells/ml, who developed an alveolar granulocytic sarcoma of the mandible. Pathological analysis of the tumor mass showed an infiltrate of immature cells which were positive for CD13, CD33, CD15, CD11b, and CD64, and negative for CD34, CD117, and HLA-DR. The patient achieved complete remission following a 1-week course of chemotherapy, however, 7 months later she developed a second granulocytic sarcoma in the left soleus muscle. The absolute CD4+ count had now reduced to 3 cells/ml with an inversion in the Th/Ts index (0.01), and she died of gram-negative sepsis 1 month later. CONCLUSIONS: Granulocytic sarcoma is extremely rare in patients with HIV. The case is discussed with reference to the literature.

An aggressive extramedullary cutaneous plasmacytoma associated with extreme alterations in the innate immune system.

BACKGROUND: The role of natural killer (NK) cells in plasma cell diseases has not yet been fully characterized. CASE REPORT: We present the case of a 47-year-old man with an extremely aggressive extramedullary plasmacytoma of the lung with associated cutaneous lesions, whose disease was accompanied by a significantly decreased number of NK cells (CD56+, CD16+, CD3-) in the peripheral blood, very low NK cell activity levels, and a decreased interleukin-2 production from cultured cells in vitro. Histology and immunohistochemistry of the lung and cutaneous lesions identified that the tumor was composed of clonal plasma cells which were CD38+++, CD138+++, lambda chain+, kappa chain-, and cytokeratin-. Bone marrow histology and cytology were initially normal. The disease progressed rapidly despite local radiotherapy and systemic chemotherapy, and the patient died shortly after diagnosis. CONCLUSIONS: Cutaneous involvement in extramedullary plasmacytoma represents a clinically aggressive variant of plasma cell tumor, which runs a rapid course and has associated devastating effects on the patient's innate immune system.

Clinical Characteristics and Treatment Outcome of Hypocellular Acute Myeloid Leukemia Based on WHO Classification.

The hypocellular acute leukemia is very rare atypical leukemia with frequency of 5-7% among patients with acute leukemias. It mainly occurs in older patients and usually has a myeloid phenotype. It is still unclear whether the outcome of hypocellular acute myeloid leukemia is less favorable than adult acute myeloid leukemia with normal cellularity. We retrospectively analyzed all hypocellular acute myeloid leukemias which were treated in 16 years period, between January 1998 and December 2014. There were 33 patients, 21 male and 12 female. The median age of the patients was 58.9 years (ranging from 19 to 88 years) and median cellularity of bone marrow was 16%. All patients presented with cytopenias with median white blood cell count 1.9 × 109/l, platelets 47.2 × 109/l and hemoglobin 85.9 g/l. Nineteen patients were treated with standard 3 + 7 protocol (daunoblastin 45 mg/m2 1, 3, 5 days, cytosin-arabinozide 100 mg/m2/12 h for 7 days), 5 patients with HDAC protocol and, 3 (9%) with low dose cytosin-arabinoside and in 6 (18.1%) patients only supportive therapy was applied. One patient died on 34 day after treatment with HiDAC, 3 patients after treatment with 3 + 7 regimen in full doses on days 23, 35, and 58 days. Complete remission was achieved in 20/33 (60.60%) patients, with median duration of 14 months. Median overall survival (OS) of the entire cohort was 16 months, and for the treated group 21 months (range 5-67 months). Median OS of patients treated with low dose cytosine-arabinoside was 6 months. The advanced age (p = 0.009, KK = - 0.46, Log rank, p = 0.031) as well as therapy options (Log rank p < 0.0001) shows a significant correlation with OS. We report a cohort of patients with hypocellular acute myeloid leukemia who responded to standard induction chemotherapy as are in standard acute myeloid leukemia.

More than a third of non-gastric malt lymphomas are disseminated at diagnosis: a single center survey.

Mucosa-associated lymphoid tissue (MALT) lymphomas are extranodal B-cell tumors that generally follow an indolent course. The gastrointestinal tract is the most common site of MALT lymphoma, comprising 50% of all cases. The tissue lesions are often localized, have high therapeutic response rates with late relapses with a long overall survival (OS). The patients with non-gastric lesions may follow a different clinical course and many of them present with disseminated disease. This study reports a series of 51 patients with non-gastric MALT lymphoma. Twenty patients (39.2%) presented with disseminated disease, seven (13.7%) patients had two MALT mucosal sites involved and eight (15.7%) had involvement of three or more mucosal sites. At presentation, 17 (33.3%) patients had the lymph node and 12 (23.5%) the bone marrow involvement. Following various combinations of treatment, complete remission was achieved in 40 (81.6%), and partial remission in three of the 49 treated patients with no difference in response rates between different disease stages. Relapse occurred in 12/43 (27.9%) patients among whom eight (18.6%) recurred in the presenting organ system. Five patients (9.8%) died because of a rapid disease progression after a median follow-up of 56 months; two patients with primary lung lesions, 1 patient with secondary intestinal disease, and 2 patients suffered transformation to diffuse large B-cell lymphoma. No significant difference in survival was found between localized and disseminated disease (log rank 0.05, df = 1, P = 0.81). A patient age > or = 60 yr at diagnosis and presentation with the nodal disease were found to be statistically significant negative prognostic factors (P < 0.05). Median OS was not reached after 145 months of follow-up, with the estimated OS being 88% at 2 yr, and 78% at 5 yr.

CD56-Positive Acute Myeloid Leukemia Following Treatment of Hairy Cell Leukemia with Cladribine - Report of 2 Cases and Review of the Literature.

Treatment of hairy cell leukemia (HCL) with alfa-interferon and purine analogs significantly prolongs survival in these patients. However, with life prolongation, an increased risk of secondary malignancies has been reported. Acute myeloid leukemia (AML), as a second malignancy after HCL treatment is extremely rare and has been reported in only 12 cases so far. We here report additional 2 cases of CD56+ AML developed after sustained clinical remission of HCL achieved with cladribine (2 and 6 years after, respectively). The first patient refused chemotherapy and shortly thereafter died. The second patient responded to chemotherapy and was successfully allo-transplanted. Three years later, the patient is in stable clinical remission, which is a unique case in the literature. In conclusion, it is not clear whether development of AML in HCL patients is caused by mutagenic potential of the applied chemotherapy or by immune suppression/ perturbations as a characteristic of the underlying disease.

Tuberculous lymphadenitis as a cause of obstructive jaundice: a case report and literature review.

Obstructive jaundice secondary to tuberculosis (TB) is extremely rare. It can be caused by TB enlargement of the head of the pancreas, TB lymphadenitis, TB stricture of the biliary tree, or a TB mass of the retroperitoneum. A 29-year-old man with no previous history of TB presented with abdominal pain, obstructive jaundice, malaise and weight loss. Ultrasonography (US), computer tomography (CT) scan and endoscopic retrograde cholangiopancreatography (ERCP) were suggestive of a stenosis of the distal common bile duct (CBD) caused by a mass in the posterior head of the pancreas. Tumor markers, CEA and CA19-9 were within normal limits. At operation, an enlarged, centrally caseous lymph node of the posterior head of the pancreas was found, causing inflammatory stenosis and a fistula with the distal CBD. The lymph node was removed and the bile duct resected and anastomosed with the Roux-en Y jejunal limb. Histology and PCR based-assay confirmed tuberculous lymphadenitis. After an uneventful postoperative recovery, the patient was treated with anti-tuberculous medication and remained well 2.5 years later. Though obstructive jaundice secondary to tuberculous lymphadenitis is rare, abdominal TB should be considered as a differential diagnosis in immunocompromised patients and in TB endemic areas. Any stenosis or fistulation into the CBD should also be taken into consideration, and biliary bypass surgery be performed to both relieve jaundice and prevent further stricture.

Elevated TNF-alpha and LDH without parathormone disturbance is associated with diffuse osteolytic lesions in leukemic transformation of myelofibrosis.

Myelofibrosis is a clonal myeloproliferative disorder characterized by splenomegaly, abnormal deposition of collagen in the bone marrow, extramedullary hematopoiesis, dacriocytosis, and leukoerythroblastic blood smear. Development and maintenance of fibrosis are mediated by a complex network of several cytokines, including tumor necrosis factor-alpha (TNF-alpha). Osteosclerosis is the most frequently observed bone change in myelofibrosis. Based on this, we present an atypical case of leukemic transformation in myelofibrosis associated with diffuse osteolytic lesions and extremely elevated TNF-alpha and lactate dehydrogenase (LDH). Parathormone was not disturbed.

Analysis of CD23 antigen expression in B-chronic lymphocytic leukaemia and its correlation with clinical parameters.

B-Chronic lymphocytic leukaemia (B-CLL) is a monoclonal malignancy characterized by an accumulation of terminally differentiated small and anergic B lymphocytes in the blood, bone marrow and other tissues. CD23 antigen, a trans-membrane glycoprotein, promotes the activation and proliferation of normal B lymphocytes and has an important role in the process of malignant transformation in B-CLL. This retrospective cohort study of 77 consecutive newly diagnosed B-CLL patients, 43 males, 34 females, median age of 62 years, examined CD23 expression and correlations with clinical parameters. CD23+ was negatively correlated with pro-lymphocyte infiltration of the bone marrow (P<0.01) and peripheral blood lymphocyte counts (P<0.001). Lower CD23 expression was correlated with lower serum immunoglobulin levels (P<0.05), especially IgG; while greater CD23 expression was positively correlated with higher CD5 levels. B-CLL patients with a percentage of CD23+ lymphocytes >40% had longer survival (92.8 months) than those expressing <40% (35.3 months) (P=0.001). CD23 is not uniformly expressed by lymphocytes in B-CLL patients, and the differences in expression are dependent on a number of clinical parameters, including the peripheral blood lymphocyte count and the degree of pro-lymphocyte infiltration of the bone marrow. CD23 expression is significantly decreased in patients with extremely high lymphocyte counts (PBL counts of >100 x 10(9)/l) and in the advanced stages of disease.

Nephrotic syndrome and acute renal failure in non-Hodgkin lymphoplasmacytic lymphoma.

Two patients with lymphoplasmacytic lymphoma, and monoclonal proteins of IgM in one, and IgG and lambda light chains in the second patient, nephrotic syndrome and acute renal failure are reported. A 58-year-old man previously treated for pre-B acute lymphoblastic leukemia, developed 3 years later nephrotic syndrome as a complication of lymphoplasmacytic lymphoma and high-paraprotein IgM kappa type. Immunofluorescent analysis of kidney biopsy showed extensive IgM and light kappa chain deposits, which caused membranoproliferative glomerulonephritis. Treatment with cyclophosphamide was ineffective and patient died 2 months later. The second patient is a 42-year-old female diagnosed with lymphoplasmacytic lymphoma and paraprotein IgG lambda type. The course of the disease was fulminant with developing nephrotic syndrome and fatal acute renal failure. Immunofluorescent and light microscopic studies of kidney biopsy showed signs of immunotactoid glomerulonephritis with deposits of IgG and C3. Hemodyalises and cytostatic therapy were without response and she died after 45 days.

Importance of early detection and follow-up of FLT3 mutations in patients with acute myeloid leukemia.

Mutations in the fms-like tyrosine kinase 3 (FLT3) gene, such as internal tandem duplication (FLT3/ITD) in the juxtamembrane domain and point mutations in the tyrosine kinase domain, are the most common abnormalities in acute myeloid leukemia (AML). FLT3/ITD and FLT3/D835 mutations were analyzed in 113 Serbian adult AML patients using polymerase chain reaction. Twenty patients were found to be FLT3/ITD positive (17.7%). The mutations occurred most frequently in M5 and M0 subtypes of AML. They were mainly associated with the normal karyotype. All patients harboring FLT3/ITD had a higher number of white blood cells than patients without it (p = 0.027). FLT3/ITD mutations were associated with lower complete remission (CR) rate (chi (2 )= 5.706; p = 0.017) and shorter overall survival (OS; Log rank = 8.76; p = 0.0031). As for disease-free survival, the difference between FLT3/ITD-positive and FLT3/ITD-negative patients was not statistically significant (Log rank = 0.78; p = 0.3764). In multivariate analysis, the presence of FLT3/ITD mutations was the most significant prognostic factor for both OS and CR rate (p = 0.0287; relative risk = 1.73; 95% CI = 1.06-2.82). However, in the group of patients with the intermediate-risk karyotype, the mere presence of FLT3/ITD was not associated with inferior clinical outcome. FLT3/D835 point mutation was found in four patients (3.5%) only. Follow-up of the FLT3/ITD-positive patients revealed stability of this mutation during the course of the disease. However, changes in the pattern of FLT3/D835 mutations in initial and relapsed AML were observed. Our results indicate an association of FLT3/ITD with the adverse outcome in AML patients treated with standard induction chemotherapy. Because FLT3/ITD mutation is a target for specific therapeutic inhibition, its early detection could be helpful in clinical practice.

Metastatic melanoma to the common bile duct causing obstructive jaundice: a case report.

Metastatic melanoma to the common bile duct is very rare with only 18 cases reported so far. We report a 46 year old women who, 18 mo after excision of a skin melanoma, developed a painless progressive obstructive jaundice. At operation a melanoma within the distal third of the common bile duct was found. There were no other secondaries within the abdomen. The common bile duct, including the tumor, was resected and anastomosed with Roux-en-Y jejunal limb. The patient survived 31 mo without any sign of local recurrence and was submitted to three other operations for axillar and brain secondaries, from which she finally died. Radical resection of metastatic melanoma to the common bile duct may result in lifelong relief of obstructive jaundice. It is safe and relatively easy to perform. In other cases, a less aggressive approach, stenting or bypass procedures, should be adopted.

Outcomes of primary thyroid non-Hodgkin's lymphoma: a series of nine consecutive cases.

Primary non-Hodgkin's lymphoma (NHL) of the thyroid gland is a rare disease with an incidence of 0.5 per 100,000 population. Stages IE and IIE thyroid NHL have been traditionally treated by surgical resection; however, modern treatment consists of chemotherapy and local radiotherapy, and surgery is often reserved for tissue diagnosis and relief of airway compression. We retrospectively reviewed the management and outcomes of nine consecutive patients with thyroid NHL, eight females and one male (median age 63 yr, range 34-71 yr) treated between 1994 and 1999. Five patients had disease stage IE and 4 stage IIE. Median follow-up was 72 mo. Pathohistology and immunohistochemistry identified two patients with mucosa-associated lymphoid tissue (MALT), three follicular center cell lymphoma (FCC), two patients large B-cell lymphoma (BLCL), one a marginal zone lymphoma (MZL), and one patient a peripheral T-cell lymphoma (PTCL). Total thyroidectomy was performed in three patients and subtotal thyroidectomy in four. One (MALT) patient underwent surgery alone; three patients surgery, radiotherapy, and chemotherapy (two FCC, one PTCL); three patients surgery and chemotherapy (one MALT, one FCC, one LBCL); and two chemotherapy alone (one LBCL, one MZL). Median survival was 79 mo (range 13-124 mo). The PTCL patient, a 34-yr-old man, died from disseminated disease at 13 mo despite secondary chemotherapy, and one LBCL patient with extensively invasive local disease died from stroke 17 mo after diagnosis. The remaining seven patients remain in remission with no local or systemic relapse at a mean of 86 mo. With appropriate therapy primary thyroid NHL has a favorable course; however, prognosis depends on the histology, local spread, and the stage of the disease at presentation, as well as the patient's performance status. Surgery in combination with chemotherapy and/or radiotherapy is still warranted for intermediate and high-grade thyroid NHLs, with over 77% of patients achieving long-term remission. Peripheral T-cell lymphoma carries a poor prognosis.