A Case of Femoral Artery Aneurysm Caused by Methotrexate Associated Lymphoproliferative Disease.

An 82-year-old man with left leg edema was referred to our department after an ultrasound examination by his previous physician, which revealed deep vein thrombosis (DVT) in the left superficial femoral vein and a left common femoral artery aneurysm (CFAA). The DVT was caused by the CFAA. The patient was adjudged to be at high risk of peripheral embolization due to the irregular shape of the varicose vein and a large amount of mural thrombus. Surgery was performed to replace the artificial blood vessel. The patient displayed firm adhesion to the surrounding area, marked lymph node swelling, and a large amount of mural thrombus in the mass. The superficial femoral artery (SFA) demonstrated severe intimal thickening and partial dissection. The postoperative course was good, and the patient was undergoing rehabilitation to be discharged home; however, B-cell lymphoma was suspected based on the pathology results of the mass wall submitted intraoperatively. The patient had a history of rheumatoid arthritis and was treated with methotrexate (MTX). During the course of his illness, a subcutaneous mass was found on his right forearm, and a skin biopsy revealed MTX-associated lymphoproliferative disease (MTX-LPD), which had resolved with MTX withdrawal. The histopathological results of the skin biopsy matched those of the CFAA mural thrombus, and Epstein-Barr virus-positive cells were also observed, leading to the diagnosis of MTX-LPD, which was considered to be the cause of CFAA. No MTX-LPD was identified in the vessel walls or intramural thrombus. We herein report a case of CFAA with an extremely rare etiology and clinical presentation.

Use of finer needles for venipuncture increases in vitro haemolysis despite reducing persistent pain and nerve injury: A retrospective study.

BACKGROUND: Although venipuncture is minimally invasive, and is the most frequently performed medical procedure, it carries the small risk of causing persistent pain, including nerve damage. Recently, our hospital stopped using 22-gauge needles for venipuncture in outpatients and switched to using only 23- and 25-gauge needles. We investigated the impact of using only the finer needles on the incidence of persistent or neuropathic pain and the prevalence of haemolysis, as well as the impact of haemolysis associated with the needle change on other laboratory data. METHODS: We retrospectively collected and analysed data on venipuncture-associated pain complaints made during the 1-year period prior and 1-year period after the change in needles, as well as the frequency of haemolysis before and after the change. We also focused on 90 cases that showed significant haemolysis after the needle change and compared the serum aspartate aminotransferase, lactate dehydrogenase, and potassium levels before and after the needle change. RESULTS: The incidence of persistent pain was significantly reduced from 1 in 10,825 venipunctures before the change to 1 in 29,747 venipunctures after the change. Notably, no patients experienced neuropathic pain after the change. However, the prevalence of haemolysis was significantly increased. Additionally, the serum aspartate aminotransferase, lactate dehydrogenase, and potassium levels were significantly elevated in the cases that showed moderate to gross haemolysis after the needle change. CONCLUSION: Using finer needles involves both advantages and disadvantages, and careful consideration is needed to determine which type of needle is in the best interests of the patient.

Pulmonary Veno-Occlusive Disease after Autologous Stem Cell Transplantation.

Pulmonary veno-occlusive disease (PVOD) is an extremely rare condition in oncology practice. Although PVOD is clinically similar to pulmonary arterial hypertension, the conditions differ in terms of pathophysiology, management, and prognosis. This report discusses the case of a 47-year-old woman who developed dyspnea and fatigue after high-dose cyclophosphamide chemotherapy and autologous hematopoietic stem cell transplantation for relapsed lymphoma. The patient exhibited tachycardia, tachypnea, and hypotension, but other findings in the physical examination were unremarkable. The imaging studies showed no evidence of pulmonary embolism, but multiple ground-glass opacities and bilateral pleural effusions were observed on chest high-resolution computed tomography scans. In the right heart catheterization study, the mean pulmonary artery pressure and pulmonary vascular resistance were 35 mm Hg and 5.93 Wood units, respectively, with a normal pulmonary capillary wedge pressure of 10 mm Hg. Pulmonary function tests revealed a remarkable reduction in the percentage predicted value of diffusing capacity of the lungs for carbon monoxide to 31%. Lymphoma progression, collagen diseases, infectious diseases such as human immunodeficiency virus or parasitic infections, portal hypertension, and congenital heart disease were carefully excluded as these are also capable of causing pulmonary arterial hypertension. Thereafter, we reached a final diagnosis of PVOD. The patient was treated with supplemental oxygen and a diuretic during 1 month of hospitalization, which relieved her right heart overload symptoms. Herein, we present the patient's clinical course and diagnostic workup because misdiagnosis or inappropriate treatment can lead to unfavorable outcomes in patients with PVOD.

[Thrombotic microangiopathy with gastrointestinal hemorrhage during carfilzomib therapy for multiple myeloma].

A 70-year-old woman was admitted to the hospital with loss of appetite and melena. She was diagnosed with multiple myeloma 7 years ago and had been on carfilzomib, lenalidomide, and dexamethasone (KRd) therapy for a month because her disease had a relapsed/refractory. On admission, her laboratory tests revealed hemolytic anemia with schizocytes, thrombocytopenia, and acute renal dysfunction. TMA (thrombotic microangiography) caused by carfilzomib was suspected. The possibility of thrombotic thrombocytopenia was considered, and steroid pulse therapy was initiated. Her condition improved significantly after she stopped taking carfilzomib, plasma exchange, hemodiafiltration, steroid pulse therapy, and abstaining from food. The previously reported cases of carfilzomib-induced TMA included fever, gastrointestinal symptoms (nausea/vomiting, diarrhea), and acute renal disorders (lower extremity edema, decreasing urine output). As far as we know, this is the first case of carfilzomib-induced TMA with bleeding as the first symptom.

Clinical entity of cytomegalovirus disease in patients with malignant lymphoma on bendamustine therapy: a single-institution experience.

We investigated the incidence, risk factors, and clinical outcomes of cytomegalovirus (CMV) disease in patients with B-cell lymphoma treated with a bendamustine-containing regimen. The incidence of CMV disease was analyzed after starting treatment with 139 regimens in 126 patients. Clinically significant CMV disease was observed in seven patients. The median duration between bendamustine initiation and the diagnosis of CMV disease was 69 d (range, 40-233), and the median of cycles completed at onset was 2 (range, 1-6). Furthermore, the incidence of CMV disease was significantly higher in the elderly patients than that in the younger patients. The target organs of CMV disease were the liver, gastrointestinal tract, lungs, and retinas. Antiviral therapy was administered to all patients. However, the recurrence of CMV disease was observed in two patients. This study provides information that could contribute to clinicians' decision-making on lymphoma therapy using bendamustine.

Clinical impact of central nervous system-directed therapies on intravascular large B-cell lymphoma: A single institution's experience.

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of B-cell lymphoma characterized by aggressive disease progression with a high incidence of central nervous system (CNS) involvement. We retrospectively analyzed 16 patients with de novo IVLBCL treated at our hospital between 2004 and 2018 with either standard therapy plus CNS-directed therapy or standard therapy alone. CNS-directed therapy was associated with a significantly better 2-year CNS-free survival (100% vs. 63%, p = 0.0191), despite no significant effects on progression-free or overall survival. Further studies should assess CNS-focused treatment in patients with IVLBCL with or without primary CNS involvement.

The relationship between new PCR positive cases and going out in public during the COVID-19 epidemic in Japan.

The suppression of the first wave of COVID-19 in Japan is assumedly attributed to people's increased risk perception after acquiring information from the government and media reports. In this study, going out in public amidst the spread of COVID-19 infections was investigated by examining new polymerase chain reaction (PCR) positive cases of COVID-19 and its relationship to four indicators of people going out in public (the people flow, the index of web searches for going outside, the number of times people browse restaurants, and the number of hotel guests, from the Regional Economic and Social Analysis System (V-RESAS). Two waves of COVID-19 infections were examined using cross-correlation analysis. In the first wave, all four indicators of going out changed to be opposite the change in new PCR positive cases, showing a lag period of -1 to +6 weeks. In the second wave, the same relationship was only observed for the index of web searches for going outside, and two indicators showed the positive lag period of +6 to +12 weeks after the change in new PCR positive cases. Moreover, each indicator in the second wave changed differently compared to the first wave. The complexity of people's behaviors around going out increased in the second wave, when policies and campaigns were implemented and people's attitudes were thought to have changed. In conclusion, the results suggest that policies may have influenced people's mobility, rather than the number of new PCR positive cases.

Ideal dose intensity of R-CHOP in diffuse large B-cell lymphoma.

INTRODUCTION: The standard of care for diffuse large B-cell lymphoma (DLBCL) is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, its ideal dose intensity varies among cases. AREAS COVERED: This review provides the latest insights on the dose intensity of R-CHOP for DLBCL patients. Specifically, we discussed the optimal dose intensity for elderly patients, the optimal number of treatment cycles for limited or advanced-stage diseases, and the role of dose-intensified therapies or adding targeted inhibitors. EXPERT OPINION: Performing a comprehensive or simplified geriatric assessment can distinguish elderly DLBCL patients who will likely benefit from curative R-CHOP. Very elderly or medically unfit patients may need dose reduction in R-CHOP; the Age, Comorbidities, and Albumin index may aid decision-making. Four cycles of R-CHOP followed by two rituximab cycles comprise a new standard for low-risk, limited-stage DLBCL patients. Compared to eight cycles, six cycles of R-CHOP have similar efficacy and fewer toxicities for advanced-stage DLBCL. Dose-intensified therapy is not recommended in most DLBCL cases but may be considered for patients with double (or triple)-hit lymphoma. Applying targeted inhibitors and not merely escalating R-CHOP dose intensity through molecular subtyping will improve the treatment outcome for DLBCL.

Diffuse large B-cell lymphoma (DLBCL) is one of the most common blood cancers. Patients with DLBCL are usually treated with a standard (immuno-) chemotherapy called R-CHOP, which stands for rituximab, cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin, and prednisone. Of these, cyclophosphamide and doxorubicin are particularly toxic but effective. Therefore, the dosages of these drugs are adjusted according to the patient's body size. However, the ideal amounts of these drugs (dose intensity) can vary from case to case. For instance, the regular dose intensity of R-CHOP is too toxic for some people, such as very older patients. Furthermore, ideal total amounts of these drugs, that is, ideal cycle numbers of R-CHOP, are also different between patients with limited disease and advanced disease. Therefore, oncology/hematology researchers have been seeking the optimal dose intensity of R-CHOP in each patient with DLBCL for years. The goal of this review is to provide the latest insights on the ideal dose intensity of R-CHOP in DLBCL treatment. In this article, we discuss: how R-CHOP was established as the standard of care for DLBCL, how to identify candidates for standard R-CHOP among older patients, how to adjust the dose intensity of R-CHOP for patients who are not candidates for standard R-CHOP, optimal cycle number of R-CHOP for limited-disease DLBCL, optimal cycle number of R-CHOP for advanced DLBCL, how to treat patients with a large mass, and the role of more intensive therapies other than R-CHOP in DLBCL treatment. Finally, we demonstrate how experts determined the dose intensity of R-CHOP for some example cases with DLBCL.

Relationship between Carnitine Deficiency and Tyrosine Kinase Inhibitor Use in Patients with Chronic Myeloid Leukemia.

BACKGROUND: Some chemotherapeutic agents cause carnitine deficiency, which causes general fatigue. However, there is no study on carnitine deficiency in patients with chronic myeloid leukemia (CML) during tyrosine kinase inhibitor (TKI) therapy. OBJECTIVE: In this study, we investigated carnitine concentrations in patients with CML receiving TKI therapy. METHOD: This study included patients with well-controlled CML. Total carnitine and free carnitine concentrations were evaluated using the enzyme cycling method. The brief fatigue inventory (BFI) and cancer fatigue scale (CFS) were used to assess general fatigue developed during TKI therapy. RESULTS: Fifty-five patients on TKI therapy were included. Of these, 12 (21.8%) patients had low free carnitine concentrations. Free carnitine concentrations were higher in men than in women. Younger age was closely associated with lower free carnitine concentrations. TKI type, TKI dose, treatment response, or therapy duration were not associated with free carnitine concentrations. None of the scores (the global fatigue score with the BFI and CFS score) correlated with carnitine concentrations. Concentrations of free carnitine in patients in the treatment-free remission group were slightly higher than those in the TKI group, with only 9.1% having a low concentration of free carnitine. CONCLUSION: Carnitine deficiency is probably not a major cause of general fatigue but may occur in patients with CML receiving TKI therapy.

Absolute Lymphocyte Counts After Lenalidomide Initiation may Predict the Prognosis of Patients With Relapsed or Refractory Multiple Myeloma.

Background/Aim: We assessed the prognosis of patients with refractory or relapsed multiple myeloma (RRMM) by focusing on the change in absolute lymphocyte counts (ALCs) after lenalidomide and dexamethasone (Ld) initiation. Patients and Methods: In total, 72 patients with RRMM were treated with Ld. ALCs were evaluated before treatment and at 1, 2, and 3 months after Ld initiation. The median ALCs in the entire cohort before and at 1, 2, 3 months after Ld initiation were 1,131, 1,059, 1,222, and 1,162/µl, respectively. Results: ALCs before Ld initiation did not affect time to next treatment (TNT) or overall survival (OS). However, the patients with ALCs equal to or greater than the median at 3 months showed relatively better TNT than those with lower lymphocyte counts, with a significant difference. OS was also significantly longer in patients with higher ALCs. Conclusion: Immunomodulation by lenalidomide may improve prognosis in patients with RRMM.

Maintenance Therapy With Bortezomib and Dexamethasone for Transplant-ineligible Patients With Multiple Myeloma.

Background/Aim: Here, we investigated whether bortezomib as a maintenance therapy affected outcomes in transplant-ineligible patients with multiple myeloma (MM). Patients and Methods: Following induction therapy with bortezomib, maintenance therapy with bortezomib (1.3 mg/m 2 ) and dexamethasone (20 mg) was administered once or twice every 4 weeks until disease progression. The endpoints of this study were time to next treatment and overall survival. Results: Seventy-six newly diagnosed, transplant-ineligible patients were treated with a bortezomib-based regimen; 28 discontinued induction therapy, 27 did not receive maintenance therapy after induction therapy (the non-maintenance group), and 21 did (the maintenance group). In the three groups, the median times to the next required treatment were 3, 14, and 37 months, respectively. The 3-year overall survival rates were 55%, 69%, and 85%, respectively. There were no significant differences in patient characteristics between the non-maintenance and maintenance groups, except for poorer estimated glomerular filtration rates in the maintenance group. Conclusion: Bortezomib maintenance therapy may be a useful option for transplant-ineligible patients with MM.

[Transformation of CD5-positive nodal marginal zone lymphoma to diffuse large B-cell lymphoma].

Nodal marginal zone lymphoma (NMZL) is a form of nodal B-cell lymphoma exhibiting proliferation of abnormal lymphocytes at the circumference of the mantle zone in the lymph nodes. Although the outcome of patients with this disease is often favorable, we recently encountered a patient with a CD5-positive NMZL who was resistant to chemotherapy. A 67-year-old woman complaining of systemic lymph node swelling was referred to our hospital. After biopsy of the neck lymph node, she was diagnosed with CD5-positive NMZL. Disease progression was revealed after 16 months, and she was initially treated with chemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisolone (R-CVP). However, this therapy was ineffective. Subsequent therapy with rituximab and bendamustine also failed to induce remission. A rebiopsy revealed that the NMZL had transformed into a diffuse large B-cell lymphoma. This patient died after 2 years from the initial diagnosis due to lymphoma progression. Cases of CD5-positive NMZL are rare; thus, it is difficult to study the clinical implications of CD5 expression in this disease. Here we describe the current understanding of CD5 expression in NMZL.

Increased Arbekacin Clearance in Patients With Febrile Neutropenia.

BACKGROUND: Arbekacin (ABK) is used to treat infections caused by methicillin-resistant Staphylococcus aureus and is used widely for the treatment of febrile neutropenia (FN). As ABK has a narrow therapeutic concentration window, the dosage must be adjusted via therapeutic drug monitoring. However, the influence of the physiology of patients with FN on the pharmacokinetic (PK) parameters of ABK remains unclear. Therefore, we examined this influence on ABK PK parameters. METHOD: We performed a retrospective cohort study using data from patients with a hematologic malignancy who were ≥18 years and had been administered ABK. We excluded patients who did not receive therapeutic drug monitoring and had an estimated glomerular filtration rate (eGFR) of <30 mL/min, because clinically sufficient data would not be available. RESULT: Of the 99 enrolled patients, 25 did not have FN and 74 had FN. Arbekacin clearance (CLabk) was shown to correlate with eGFR in patients with FN (r = 0.32, P = 0.0062) and without FN (r = 0.50, P = 0.01). CLabk was higher in patients with FN than in those without FN. In addition, in the eGFR of <100 mL/min group (normal renal function), CLabk and CLabk/eGFR were also higher in patients with FN than in those without FN. CONCLUSIONS: CLabk was increased in patients with FN and normal renal function; therefore, we propose an increased ABK dose for patients with FN and normal renal function.

MPC-1 expression in myeloma cells is associated with the efficacy of bortezomib therapy.

The use of bortezomib in the clinic has significantly improved outcomes for patients with multiple myeloma (MM), even those harboring high-risk cytogenetic abnormalities or those classified in the high-risk category according to the International Staging System (ISS). In this study, we analyzed the association between immunophenotyping on myeloma cells and the clinical outcomes of patients who received bortezomib-based regimens as first-line therapy. Immunophenotypic analysis before bortezomib therapy was performed by flow cytometry, and whether the immunophenotyping results influenced the clinical outcomes of the patients was investigated. Seventy-four newly diagnosed patients with MM were included in this study. We found that the expression of MPC-1 significantly predicted the time to next therapy (TNT), with a longer TNT in the MPC-1 positive group (p = 0.005), whereas it did not affect overall survival (OS; p = 0.773). In addition, we found that CD45-positivity was associated with shorter TNT (p = 0.0432). Following ISS assessment at treatment initiation, patients who were classified as stage I showed a slightly longer OS compared to those at stage II or III; however, these results were not significant (p = 0.0987). Furthermore, multivariate analysis revealed the prognostic significance of MPC-1 expression, as MPC-1-negativity was associated with a worse TNT. The combination of MPC-1 and CD45 status more sensibly predicted the TNT for bortezomib therapy. Our results demonstrate the clinical importance of immunophenotyping on myeloma cells to determine patient prognoses in this era of novel therapeutic agents.

[Acute sensory neuropathy associated with Hodgkin's lymphoma: a case study].

The case of a 17-year-old man with Hodgkin's lymphoma who presented with paraneoplastic sensory neuropathy is presented. The patient visited our hospital because of acute progression of dysesthesiae in the bilateral face and extremities. He also developed an ataxic gait due to decreased deep sensation. Post-contrast T1-weighted MRI showed enhancement of both trigeminal nerves and the cauda equina. Cerebrospinal fluid examination was unremarkable. Intravenous immunoglobulin therapy and subsequent steroid pulse therapy did not improve his symptoms. Laboratory data showed an elevated serum soluble interleukin-2 receptor level. His chest X-ray and CT showed enlarged lymph nodes in the mediastinum, and the histopathologic examination of a lymph node biopsy specimen showed classical Hodgkin's lymphoma. He was treated with chemotherapy. His symptoms of neuropathy improved promptly while the lymphoma was being successfully treated, and he was able to walk with a cane. The present case was characterized by paraneoplastic sensory neuropathy as the initial clinical feature in association with Hodgkin's lymphoma. It is necessary to consider a paraneoplastic neurological syndrome even in a young patient with acute/subacute sensory neuropathy. Paraneoplastic sensory neuropathy associated with Hodgkin's lymphoma could be expected to improve with oncotherapy, and examination of the malignancy and early treatment are important.

A novel fusion gene involving PDGFRB and GCC2 in a chronic eosinophilic leukemia patient harboring t(2;5)(q37;q31).

BACKGROUND: Platelet-derived growth factor receptor beta (PDGFRB) rearrangement has been reported in a number of patients with chronic eosinophilic leukemia (CEL), B-acute lymphoblastic leukemia, myeloproliferative neoplasms, and juvenile myelomonocytic leukemia. Here, we report a case of CEL carrying a novel fusion gene involving PDGFRB and GRIP and coiled-coil domain containing 2 (GCC2). PATIENT AND METHODS: A 54-year-old man presenting with a cough and dyspnea was diagnosed with acute eosinophilic pneumonia. Cytogenetic analysis of the bone marrow revealed the presence of t(2;5)(q37;q31). Fluorescence in situ hybridization analysis in the peripheral blood leukocytes revealed the presence of a split signal at PDGFRB gene. Imatinib treatment was effective, and disappearance of t(2;5)(q37;q31) in the bone marrow was confirmed after three months of imatinib therapy. Whole-genome sequencing was performed in peripheral blood leukocytes collected before imatinib therapy. RESULTS: A novel fusion gene between exon 22 of GCC2 and exon 12 of PDGFRB was detected and the presence of GCC2-PDGFRB was confirmed by PCR. CONCLUSION: This is the first case report demonstrating the GCC2 gene as a partner of PDGFRB in the pathogenesis of CEL.

Conjunctival lymphomas in Japanese monozygotic twins: A case report.

An individual with a twin who has developed leukemia or non-Hodgkin lymphoma (NHL) has an increased risk of developing the same disease, particularly with monozygotic twins. The few reported pairs of twins who developed NHL had similar primary sites and pathological subtypes. Here, we present the first reported cases of primary conjunctival NHL in both female monozygotic twins. Twin 1 was diagnosed with an extranodal marginal zone lymphoma (EMZL; Ann Arbor stage IE) in the right conjunctiva at 25 years old and a subsequent tumor in the left conjunctiva at 39 years, and was also histopathologically diagnosed as EMZL. No infiltration of other organs was detected and both lesions were surgically excised. At the age of 40 years, Twin 2 was diagnosed with an EMZL (Ann Arbor stage IE) in the right conjunctiva without infiltration of other organs and was treated with external beam radiation therapy rather than surgery. Complete remission was achieved in both twins; neither developed conjunctival recurrences. This study highlights the importance of examining the other, apparently healthy twin when one twin develops conjunctival lymphoma.

Thrombopoietin Levels During Tyrosine Kinase Inhibitor Therapy for Chronic Myeloid Leukemia.

BACKGROUND AND OBJECTIVE: Although it is well known that platelet depletion is one of the major adverse events related to tyrosine kinase inhibitor (TKI) therapy, the effect of TKIs on thrombopoietin (TPO), a stimulating factor for thrombopoiesis, has not been examined to date. In this study, we investigated the effect of TKIs on the levels of plasma TPO concentration in patients with well-controlled chronic myeloid leukemia receiving imatinib or dasatinib and those in treatment-free remission (TFR). METHODS: Blood samples for blood cell counts and plasma TPO levels were obtained from 23 dasatinib-treated patients before and 1 h after intake, 11 patients treated with imatinib before and 2 h after intake, and nine TFR patients. Levels of plasma TPO were determined by using enzyme-linked immunosorbent assays. RESULTS: Levels of TPO were significantly inversely correlated with platelet counts in the entire cohort (r = - 0.568, p < 0.0001). Dasatinib intake, but not imatinib, significantly reduced platelet counts after intake (p = 0.0009 in dasatinib and p = 0.5431 in imatinib). However, imatinib and dasatinib intake increased the levels of TPO in these patients (p = 0.0024, dasatinib; p = 0.0098, imatinib). CONCLUSIONS: Our study results suggest that neither dasatinib nor imatinib therapy inhibits TPO production. Rather, transient increases in TPO levels seen with these two treatments might be a result of the decrease in TPO clearance these TKIs confer. However, further investigations are required to clarify the effect of TKIs on thrombopoiesis.