Chylothorax: A Tangled Road to Definitive Diagnosis of Non-Hodgkin Lymphoma.

BACKGROUND Chylothorax is a rare condition caused by the leak of chyle into the pleural cavity. Malignancy, especially advanced lymphomas, are the most common non-traumatic causes of chylothorax. When thoracentesis and the following pleural effusion studies reveal the fluid to be a chyle, it is important to look at the patients' history and understand the possible etiological factors, as the appropriate management can differ. In some instances, the true reason behind the chylothorax can be a diagnostic challenge, as presented in this case. CASE REPORT We report a case of a patient in her 70s presenting with progressive dyspnea at rest and non-productive cough. A chest X-ray showed subtotal right pleural effusion that was revealed to be a chylothorax. A CT scan was performed and revealed mediastinal, abdominal, and retroperitoneal lymphadenopathy, that, compared to the CT results 6 years ago, when for the first time enlarged lymph nodes were discovered by thyroid ultrasound, was without any progression. Initial diagnostic tests were inconclusive, and the goal was to rule out other differential diagnoses while maintaining a minimally invasive diagnostic approach. A video-assisted thoracoscopic surgery with mediastinal lymph node dissection and biopsy led to a diagnosis of follicular lymphoma. CONCLUSIONS This clinical case highlights not only an uncommon follicular lymphoma complication but also is an example of a diagnostic challenge due to certain clinical features being misleading from the true cause of the chylothorax. After a wide variety of investigations were applied, the patient was finally diagnosed with non-Hodgkin lymphoma. Successful treatment led to a full metabolic remission.

Intracerebral Plasmacytoma in a Patient with HIV-1 Infection and SARS-CoV-2 Superinfection.

We present a rare case of intracranial solitary plasmacytoma arising in brain parenchyma in the basal nuclei. Clinical management and autopsy results of the case are described. Background: Intracranial plasmacytomas arising from brain parenchyma are extremely rare, and data from the literature are limited. Primary intracranial plasmacytomas are rare because plasma cells are not found in the brain in normal conditions. Commonly, intracranial plasmacytoma is associated with multiple myeloma, which is why multiple myeloma must be ruled out to diagnose solitary intracranial plasmacytoma. Considering that solitary plasmacytoma and multiple myeloma have some histopathological similarities, it is important to differentiate them because their respective treatments and prognoses are different. Imaging features of primary extramedullary plasmacytoma are nonspecific but are compatible with solid tumors with invariable enhancement. Plasmacytoma was aggressive because it was not diagnosed after the first MRI, but 1.5 months later, MRI showed a large object. We present a rare case of intracranial solitary plasmacytoma arising in brain parenchyma in the basal nuclei.

Chronic Thromboembolic Pulmonary Hypertension Mimicking Acute Pulmonary Embolism: A Case Report.

BACKGROUND Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare form of pulmonary hypertension which is often caused by recurrent emboli. The reported prevalence in Latvia is 15.7 cases per million inhabitants. Several risk factors predispose patients to develop chronic thromboembolic pulmonary hypertension, including the presence of chronic myeloproliferative diseases and splenectomy. CASE REPORT We present a case of a 68-year-old woman with a variant of chronic myeloproliferative disease, essential thrombocythemia, splenectomy, and chronic thromboembolic pulmonary hypertension, in whom chronic thromboembolic pulmonary hypertension was mimicking acute pulmonary embolism. On admission, the patient had progressive dyspnea, elevated right ventricular systolic pressure (RVSP) 60-70 mmHg, and elevated thrombocytes, C-reactive protein, BNP, and d-dimer levels. These results, as well as the results of thoracic computed tomography angiography with contrast, supported the diagnosis of acute pulmonary embolism. During the sequent follow-up visit after 3 months of effective anticoagulant therapy, the patient had elevated RVSP: 55-60 mmHg. Therefore, right heart catheterization was performed, in which it was found that mPAP was 37 mmHg with PCWP 5 mm Hg and PVR 8.9 Wood units, confirming the CTEPH diagnosis. CONCLUSIONS Patients who are at high risk of thrombosis need an increased level of monitoring to be properly evaluated. An easy solution to misdiagnosis of CTEPH with an acute pulmonary embolism could be taking scrupulous patient history, which can reveal multiple risk factors of CTEPH development. The subsequent assessment of risk factors can lead to a more appropriate consideration of CTEPH diagnosis vs acute pulmonary embolism.

Chemokine Receptors CCR1 and CCR2 on Peripheral Blood Mononuclear Cells of Newly Diagnosed Patients with the CD38-Positive Chronic Lymphocytic Leukemia.

Chemokines and their receptors direct migration and infiltration of immune cells. CCR1 and CCR2 maintain sequence similarity and respond to a number of the same chemokines secreted in lymphoid organs. Expression of CD38 on leukemic cells has been associated with poor clinical outcomes in patients with chronic lymphocytic leukemia (CLL) and is considered as the negative predictor of progression. In our study of newly diagnosed CLL patients, which included 39 CD38-positive and 22 CD38-negative patients, CCR1 and/or CCR2 were always detected, using flow cytometry, on the peripheral blood (PB) CD19+CD5+ lymphocytes in patients with >30% of the CD38+ CD19+CD5+ lymphocytes (n = 16). Spearman's rank correlation analysis determined correlations between the frequency of the CCR1- and CCR2-expressing PB CD19+CD5+ lymphocytes and the frequency of the CD38-positive CD19+CD5+ lymphocytes (rs = 0.50 and rs = 0.38, respectively). No significant correlations were observed between ZAP70 mRNA expression levels in PB mononuclear cells and the frequency of the circulating CCR1+ or CCR2+ CD19+CD5+ lymphocytes. Further association studies are needed to verify prognostic relevance of the CCR1/CCR2 expression on leukemic cells in CLL patients at diagnosis. We suggest that CCR1/CCR2 signaling pathways could represent attractive targets for development of CLL anti-progression therapeutics.

Diagnostic Challenges and Treatment Options for Cutaneous T Cell Pseudolymphoma: A Case Study with Rituximab Treatment.

BACKGROUND Pseudolymphoma is a rare disorder that can mimic lymphoma both clinically and histologically. It usually affects middle-aged females. Since pseudolymphoma is a rare disorder not only is diagnosing the condition difficult, but there is also a lack of standardized treatment guidelines. In the literature, anti-CD20 monoclonal antibody rituximab is described as an effective treatment option. CASE REPORT 46-year-old female fell ill suddenly with swelling and enlargement of her chin. Multiple skin biopsies were done, which were re-evaluated multiple times as well. Each ended with a new diagnosis for the patient. Finally, in the last revision of biopsy material, pseudolymphoma was confirmed. The patient received multiple courses of corticosteroid treatments - locally and systemically - without long lasting effect. After diagnosis of pseudolymphoma, the patient was started on intravenous rituximab and this treatment was effective. CONCLUSIONS Cutaneous pseudolymphoma is a diagnostic challenge. Rituximab is a treatment option for refractory pseudolymphoma. Since there are no treatment guidelines for pseudolymphoma, more clinical studies are needed to establish best treatment options for these patients. Therefore, each reported clinical case is important.

A population based study of multiple myeloma patients with medication-related osteonecrosis of the jaw.

OBJECTIVE: Medication-related osteonecrosis of the jaw (MRONJ) is a rare complication of antiresorptive or antiangiogenetic therapy that manifests as an exposed bone with clinical signs of infection, persisting for more than 8 weeks, without history of radiation therapy or metastases to the jaws. The aim of the study was to describe the incidence, risk factors, staging process and clinical course of MRONJ in patients with multiple myeloma (MM). MATERIALS AND METHODS: We retrospectively analyzed all (126) newly diagnosed MM patients at Riga East Clinical University Hospital (Riga. Latvia) from June 2014 to June 2017. RESULTS: Among 88 MM patients treated with bisphosphonates (BP), 6 (6.8%) patients developed MRONJ. All six patients received intravenous nitrogen-containing BPs. The average time until MRONJ manifestation was under two years. For our patients the severity of MRONJ was stage I in two, stage II in three, and stage III in one patient. Five patients had MRONJ of mandibula and one of maxilla. All patients with MRONJ had undergone a dental extraction or a trauma before the development of MRONJ. CONCLUSION: We found that MRONJ correlated with the patient's age. The average time until MRONJ manifestation in reserach group is 2 years. One of triggerring MRONJ factors are tooth extraction or trauma.

Chronic Thromboembolic Pulmonary Hypertension and Antiphospholipid Syndrome with Immune Thrombocytopenia: A Case Report.

BACKGROUND Antiphospholipid syndrome is an autoimmune disorder characterized by a hypercoagulable state associated with circulating antiphospholipid antibodies. The presence of antiphospholipid antibodies can result in a variety of clinical symptoms, such as thrombocytopenia, stillbirth, endocardial pathologies, and recurrent pulmonary embolism. CASE REPORT We present the case of a 23-year-old man with antiphospholipid syndrome and chronic thromboembolic pulmonary hypertension who developed severe thrombocytopenia. The patient died from right heart failure before the thrombocytopenia could be managed, preventing performance of a pulmonary endarterectomy procedure. CONCLUSIONS Managing platelet counts in patients with antiphospholipid syndrome prior to major surgery is very problematic, and requires similar treatment strategy as in patients with immune thrombocytic thrombocytopenia. Platelet transfusions may further decrease platelet count, as it can trigger formation of new antibodies.

Multiple Myeloma Treatment in Real-world Clinical Practice: Results of a Prospective, Multinational, Noninterventional Study.

BACKGROUND: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. PATIENTS AND METHODS: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months. RESULTS: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide. CONCLUSION: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits.

Pulmonary arterial hypertension in a patient treated with dasatinib: a case report.

BACKGROUND: There have been several reports on dasatinib-induced reversible pulmonary hypertension. This is the first reported case in Latvia; the patient did not discontinue the drug after the first adverse effects in the form of pleural effusions, which we speculate led only to partial reversion of the disease. CASE PRESENTATION: A 67-year-old white man with chronic myelogenous leukemia was treated with the dual Src and BCR-ABL tyrosine kinase inhibitor dasatinib. After treatment with dasatinib he had multiple pleural effusions which were suspected to be caused by congestive heart failure. Later a transthoracic Doppler echocardiography and right-sided heart catheterization revealed severe pulmonary hypertension with pulmonary vascular resistance of 12 Wood units and mean pulmonary artery pressure of 53 mmHg. Computed tomography ruled out a possible pulmonary embolism; laboratory specific tests for human immunodeficiency virus, rheumatoid factor, and anti-nuclear antibodies were negative, and dasatinib-induced pulmonary arterial hypertension was diagnosed. A follow-up right-sided heart catheterization and 6-minute walk test done a month after the discontinuation of dasatinib showed significant improvement: mean pulmonary artery pressure of 34 mmHg and pulmonary vascular resistance of 4 Wood units. CONCLUSIONS: Patients should always be closely monitored when using dasatinib for a prolonged time. Dasatinib-induced pulmonary hypertension may be fully reversible after the therapy is suspended, but the key factors involved are still unclear and need to be further studied.

Klippel-Trenaunay-Weber syndrome with atypical presentation of hypersplenism and nephrotic syndrome: a case report.

BACKGROUND: Klippel-Trenaunay-Weber syndrome is a rare syndrome; unfortunately, very few studies of the connection between hypersplenism, nephrotic syndrome, and Klippel-Trenaunay-Weber syndrome have been published. CASE PRESENTATION: We report the case of a 40-year-old white man with a typical clinical presentation of Klippel-Trenaunay-Weber syndrome, including "port-wine stains," varicose veins, hypertrophy of lower extremities, and arteriovenous fistula, as well as an unfortunate development of hypersplenism and nephrotic syndrome. CONCLUSIONS: This case report described considerable atypical relevance of Klippel-Trenaunay-Weber syndrome and hypersplenism together with nephrotic syndrome. A multidisciplinary approach was made. Unfortunately, hypersplenism is characterized by pancytopenia that suggests splenectomy, whereas nephrotic syndrome is an indication for renal biopsy; the splenectomy and renal biopsy were delayed due to our patient's severe condition. Deeper analysis including study of other patients with Klippel-Trenaunay-Weber syndrome would help us to understand the connection between elevated spleen and liver sizes, nephrotic syndrome, and Klippel-Trenaunay-Weber syndrome.

Relationship between beta-herpesviruses reactivation and development of complications after autologous peripheral blood stem cell transplantation.

The relationship between beta-herpesviruses reactivation and the development of complications after autologous peripheral blood stem cell transplantation was investigated. Viral genomic sequences were detected by the polymerase chain reaction, virus-specific antibodies by ELISA, and human herpesvirus (HHV)-6 variants by restriction endonuclease analysis. Virus reactivation, serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, soluble IL-2 receptor (sIL-2R), IL-2, and IL-4 were compared with clinical features in 44 patients before and after transplantation. Anti-CMV and anti-HHV-6 antibodies were found in 70.5% and 81.8% of patients, respectively. The frequency of plasma viremia was significantly higher in patients after transplantation (41% vs. 11.4%). Reactivation of more than one virus was identified in 55.6% of patients and reactivation of HHV-7 alone in 44.4%. In cases of concurrent infection, HHV-7 was reactivated before HHV-6, and both HHV-6 and HHV-7 were reactivated before CMV. There was a significant increase in HHV-6 load in peripheral blood leukocytes DNA during viremia. In all cases HHV-6B variant was detected. Complications after transplantation occurred in 27.3% of patients and virus reactivation was detected in all patients with complications. The significant increases in the rate of HHV-6 and HHV-7 reactivation and in serum levels of TNF-α, IL-1ß, and sIL-2R, as well as aggravated immunosuppression, suggest that both viruses were involved in the complications after autologous peripheral blood stem cell transplantation, via their immunomodulatory activity. The kinetics of reactivation suggests a potential role of HHV-7 as a co-factor of HHV-6 reactivation, and of both HHV-6 and HHV-7 as co-factors of CMV reactivation.

High-dose imatinib induction followed by standard-dose maintenance in pre-treated chronic phase chronic myeloid leukemia patients--final analysis of a randomized, multicenter, phase III trial.

BACKGROUND: Previous data suggest that the response of chronic myeloid leukemia cells to imatinib is dose-dependent. The potential benefit of initial dose intensification of imatinib in pre-treated patients with chronic phase chronic myeloid leukemia remains unknown. DESIGN AND METHODS: Two hundred and twenty-seven pre-treated patients with chronic myeloid leukemia in chronic phase were randomly assigned to continuous treatment with a standard dose of imatinib (400 mg/day; n=113) or to 6 months of high-dose induction with imatinib (800 mg/day) followed by a standard dose of imatinib as maintenance therapy (n=114). RESULTS: The rates of major and complete cytogenetic responses were significantly higher in the high-dose arm than in the standard-dose arm at both 3 and 6 months (major cytogenetic responses: 36.8% versus 21.2%, P=0.01 and 50.0% versus 34.5%, P=0.018; complete cytogenetic responses: 22.8% versus 6.2%, P<0.001 and 40.4% versus 16.8%, P<0.001) on the basis of an intention-to-treat analysis. At 12 months, the difference between treatment arms remained statistically significant for complete cytogenetic responses (40.4% versus 24.8%, P=0.012) but not for major cytogenetic responses (49.1% versus 44.2%, P=0.462). The rate of major molecular responses was also significantly better at 3 and 6 months in the high-dose arm (month 3: 14.9% versus 3.5%, P=0.003; month 6: 32.5% versus 8.8%, P<0.001). Overall and progression-free survival rates were comparable between arms, but event-free survival was significantly worse in the high-dose arm (P=0.014). CONCLUSIONS: Standard-dose imatinib remains the standard of care for pre-treated patients with chronic phase chronic myeloid leukemia (Clinicaltrials.gov identifier: NCT00327262).

High-dose imatinib improves cytogenetic and molecular remissions in patients with pretreated Philadelphia-positive, BCR-ABL-positive chronic phase chronic myeloid leukemia: first results from the randomized CELSG phase III CML 11 "ISTAHIT" study.

BACKGROUND: Imatinib 400 mg/day is the standard treatment for patients with chronic phase chronic myeloid leukemia. Recent reports suggested higher and more rapid cytogenetic and molecular responses with higher doses of imatinib. DESIGN AND METHODS: In this prospective international, multicenter phase III study, 227 patients with pre-treated Philadelphia chromosome-positive, BCR-ABL-positive chronic myeloid leukemia were randomized to a standard-dose imatinib arm (400 mg/day) or a high-dose imatinib arm (800 mg/day for 6 months followed by 400 mg/day as maintenance therapy). In this planned interim analysis hematologic, cytogenetic and molecular responses as well as toxicity were evaluated. RESULTS: Compared to the standard-dose, high-dose imatinib led to higher rates of major and complete cytogenetic responses at both 3 months (major: 21% versus 37%, P=0.01; complete: 6% versus 25%, P<0.001) and 6 months (major: 34% versus 54%, P=0.009; complete: 20% versus 44%, P<0.001). This was paralleled by a significantly higher major molecular response rate at 6 months in the high-dose imatinib arm (11.8% versus 30.4%; P=0.003). At 12 months, the rates of major cytogenetic response (the primary end-point) were comparable between the two arms (57% versus 59%). In contrast to non-hematologic toxicities, grade 3/4 hematologic toxicities were more common in the high-dose arm. Cumulative complete cytogenetic response rates were higher in patients without dose reduction in the high-dose arm (61%) than in the patients with no dose reduction in the standard-dose arm (36%) (P=0.014). CONCLUSIONS: This is the first randomized phase III trial in patients with pre-treated chronic phase chronic myeloid leukemia demonstrating improvements in major cytogenetic response, complete cytogenetic response and major molecular response rates with high-dose imatinib therapy (ClinicalTrials.gov Identifier: NCT00327262).

Single-tube nested quantitative PCR: a rational and sensitive technique for detection of retroviral DNA. Application to RERV-H/HRV-5 and confirmation of its rabbit origin.

It was reported earlier that a few patients suffering from non-Hodgkin's lymphoma had low amounts of DNA from the so-called fifth human exogenous retrovirus, HRV-5. A sensitive and rational method for large-scale screening for HRV-5 DNA was therefore developed. It is a single-tube nested quantitative PCR (stnQPCR), which uses two functionally isolated primer pairs and one probe target distinct from related endogenous retroviral sequences, yet encompassing known HRV-5 variation, allowing optimal use of sequence conservation. DNA from lymphoma, myeloma, and follicular dendritic cell lines was tested for HRV-5 positivity, as was DNA from whole blood of blood donors, non-Hodgkin's lymphoma and systemic lupus erythematosus patients, as well as DNA from lymph node biopsies of rheumatoid arthritis patients with lymphoma. One blood donor, one systemic lupus erythematosus patient, two previously known positive non-Hodgkin's lymphoma patients, and one rheumatoid arthritis lymphoma patient, came out positive. They had 24, 2, 148, 480 and 30 proviral copies per microg of DNA from PBMC or lymphoma tissue, respectively. During the completion of this work it was reported that HRV-5 is a rabbit endogenous retrovirus (RERV-H), and that HRV-5 positivity was due to presence of rabbit DNA. DNA from six RERV-H/HRV-5 positive samples was therefore retested. Three also contained rabbit mitochondrial DNA. A search for HRV-5 antibodies using synthetic peptides was negative in sera from three RERV-H/HRV-5 positive individuals, as well as in 144 other sera, according with a noninfectious origin of the RERV-H/HRV-5 DNA in human samples. A search for possible sources of rabbit DNA contamination was negative. Methods for prevention of PCR contamination were strictly adhered to. Three samples from RERV-H/HRV-5 positive individuals positive at the Uppsala laboratory were retested at one or two other laboratories, and all three were positive. Two other samples, which were positive in the Riga laboratory, were tested also in London and also found positive. One non-Hodgkin's lymphoma patient was RERV-H/HRV-5 positive in four consecutive samples, showing that positivity was a property of that patient. It is concluded that the stnQPCR developed to detect and quantify minute amounts of RERV-H/HRV-5 DNA is a principle which can be applied widely and HRV-5 is a RERV-H. Its presence in a few human blood samples could not be explained.