Multiple myeloma occurs primarily in elderly patients. Considering the high prevalence of comorbidities, comorbidity is an important issue for the management of myeloma. However, the impact of comorbidity on clinical outcomes has not been fully investigated. We retrospectively analyzed patients with newly diagnosed myeloma. Comorbidities were assessed based on the Charlson comorbidity index (CCI) and the Freiburg comorbidity index (FCI). The CCI is a summary measure of 19 comorbid conditions. FCI is determined by performance status, renal impairment, and lung disease. This study included 127 patients with a median age of 71 years. Approximately half of the patients had additional disorders at the time of diagnosis, and diabetes mellitus was the most frequent diagnosis (18.9%). The most significant factors for prognosis among patient-related conditions were a history of solid cancer and performance status (ECOG ≥ 2). The FCI score was divided into 3 groups (0, 1, and 2-3), and the CCI score was divided into 2 groups (2-3 and ≥4). FCI was a strong prognostic tool for OS (P > 0.001) and predicted clinical outcome better than CCI (P = 0.059). In conclusion, FCI was more useful than CCI in predicting overall survival in elderly patients with myeloma.
Waldenström's macroglobulinemia (WM) is a B-cell proliferative malignancy characterized by immunoglobulin M monoclonal gammopathy and bone marrow infiltration by lymphoplasmacytic cells. Clinical features and cytogenetics of WM in Asia including Republic of Korea remain unclear. Moreover, no study has reported treatment outcomes in patients with WM treated with novel agent combined with conventional chemotherapy. This study investigated clinical features and assessed treatment outcomes with novel agent and conventional chemotherapy in Republic of Korea. Data from all (n = 71) patients with newly diagnosed WM at 17 hospitals who received chemotherapy between January 2005 and December 2012 were collected retrospectively. The median age of patients was 66 years (range: 37–92 years) and male to female ratio was 5 : 1. Patients treated with novel agent combined chemotherapy displayed higher overall response rate (ORR) compared to conventional chemotherapy alone (92.9% versus 52.6%, P = 0.006). The 5-year overall survival rate was 62.6% (95% confidence interval: 34.73–111.07). Use of novel agents produced higher ORR but survival benefit was not apparent due to the small number of patients and short follow-up duration. Further studies are needed to confirm the efficacy of novel agents in patients with WM.
Therapy-related myeloid neoplasms (t-MN) occur as late complications of cytotoxic therapy. This study reviewed clinical and cytogenetic characteristics of patients with t-MN at a single institution in Korea.
The study subjects included 39 consecutive patients diagnosed with t-MN. Each subject's clinical history of previous diseases, treatments, and laboratory data was reviewed, including cytogenetics. The primary diagnosis was hematologic malignancy in 14 patients and solid tumor in 25 patients.
Therapy-related acute myeloid leukemia (t-AML, 66.7%) was found to be more common than therapy-related myelodysplastic syndrome (t-MDS). Primary hematologic malignancies that were commonly implicated included mature B-cell neoplasm and acute leukemia. Breast cancer was the most common primary solid tumor. The mean time interval from cytotoxic therapy initiation to t-MN detection was 49 months. Chromosomal aberrations were observed in 35 patients, and loss of chromosome 5, 7, or both accounted for 41% of all cases. Balanced rearrangements occurred in 13 patients; these patients showed shorter latency intervals (mean, 38 months) than patients with loss of chromosome 5 or 7 (mean, 61 months).
In this study, we determined the clinical and cytogenetic characteristics of Korean patients with t-MN. Although our results were generally consistent with those of previous reports, we found that t-MN resulting from de novo leukemia was common and that t-AML was more common than t-MDS at presentation. Multi-institutional studies involving a larger number of patients and additional parameters are required to investigate the epidemiology, genetic predisposition, and survival rate of t-MN in Korea.
Therapy-related neoplasms; Myelodysplastic syndrome; Acute myeloid leukemia; Cytogenetics; Korea
Novel agents to treat multiple myeloma (MM) have increased complete respone (CR) rates compared with conventional chemotherapy, and the quality of the response to treatment has been correlated with survival. The purpose of our study was to show how of early response to bortezomib combined chemotherapy influences survival in patients with newly diagnosed MM who are ineligible for stem cell transplantation. We assessed patient responses to at least four cycles of bortezomib using the International Myeloma Working Group response criteria. The endpoints were comparisons of progression free survival (PFS) and overall survival (OS) between early good response group (A group) and poor response group (B group). We retrospectively analyzed data from 129 patients registered by the Korean Multiple Myeloma Working Party, a nationwide registration of MM patients. The 3 yr PFS for the A and B groups was 55.6% and 18.4%, respectively (P < 0.001). The 3 yr OS for the A and B groups was 65.3% and 52.9%, respectively (P = 0.078). The early response to at least four cycle of bortezomib before next chemotherapy may help predict PFS in patients with MM who are ineligible stem cell transplantation.
Early Response; Multiple Myeloma; Bortezomib; Survival
Invasive pulmonary aspergillosis (IPA) is one of the major complications encountered by patients receiving chemotherapy for hematologic malignancies. The prolonged period of intense immunosuppression following allogeneic hematopoietic stem cell transplantation (HSCT) may increase the risk of IPA recurrence in patients with a history of IPA. We evaluated the impact of a history of IPA on allogeneic HSCT outcome, and examined the incidence of IPA after HSCT.
This retrospective study included 22 patients with a history of IPA prior to receiving allogeneic HSCT at the Samsung Medical Center from 1995 to 2007. Diagnosis of IPA was defined as proven (N=5), probable (N=0), or possible (N=17).
All 22 patients received amphotericin-based regimens to treat pre-transplant IPA. Secondary antifungal prophylaxis was administered to 10 patients during HSCT. The development of post-transplant IPA was observed in 2 patients. One of the patients died from septic shock within 2 days of the diagnosis of possible IPA. The other patient recovered from IPA, but eventually had a relapse of the primary disease. Of the 22 patients, the overall 2-year survival rate was 63% (95% confidence interval [CI]: 41-85), and the transplant-related mortality rate was 19% (95% CI: 0-38).
Our results suggest that a history of IPA prior to HSCT does not have an adverse impact on transplant outcomes, although the small number of cases was a limitation in this study. Future studies involving a larger number of cases are needed to further examine this issue.
Invasive pulmonary aspergillosis; Allogeneic hematopoietic stem cell transplantation
Based on the data obtained through Child Protective Services (CPS) case records abstraction, this study aimed to explore patterns of overlapping types of child maltreatment in a sample of urban, ethnically diverse male and female youth (n= 303) identified as maltreated by a large public child welfare agency.
A cluster analysis was conducted on data for 303 maltreated youth. The overall categorization of four types of abuse (i.e., physical, sexual, emotional abuse and neglect) was used to provide a starting point for clustering of the 303 cases and then the subtypes of emotional abuse were broken down in the clusters. The different clusters of child maltreatment were compared on the multiple outcomes such as mental health, behavior problems, self-perception, and cognitive development.
In this study, we identified four clusters of child maltreatment experiences. Three patterns involved emotional abuse. One cluster of children experienced all four types. Different clusters were differentially associated with multiple outcome measures. In general, multiply-maltreated youth fared worst, especially when the cluster involved sexual abuse. Also, sex differences were found in these associations. Boys who experienced multiple types of maltreatment showed more difficulties than girls.
Conclusion & practice implications
These results reiterate the importance of creating more complex models of child maltreatment. Children who have experienced various types of maltreatment are especially in need of more attention from professionals and resources should be allocated accordingly.
We investigate cytotoxicity and mechanism of action of AS703026, a novel, selective, orally bioavailable MEK1/2 inhibitor, in human multiple myeloma (MM). AS703026, more potently (9-10 fold) than AZD6244, inhibited growth and survival of MM cells and cytokine-induced osteoclast differentiation. Inhibition of proliferation induced by AS703026 was mediated by G0-G1 cell cycle arrest and was accompanied by reduction of c-maf oncogene expression. AS703026 further induced apoptosis via caspase 3 and PARP cleavage in MM cells, both in the presence or absence of bone marrow stromal cells (BMSCs). Importantly, AS703026 sensitized MM cells to a broad spectrum of conventional (dexamethasone, melphalan), novel or emerging (lenalidomide, perifosine, bortezomib, rapamycin) anti-MM therapies. Significant tumor growth reduction in AS703026- vs. vehicle-treated mice bearing H929 MM xenograft tumors correlated with downregulated pERK1/2, induced PARP cleavage, and decreased microvessels in vivo. Moreover, AS703026 (<200 nM) was cytotoxic against the majority of tumor cells tested from patients with relapsed and refractory MM (84%), regardless of mutational status of RAS and BRAF genes. Importantly, BMSC-induced viability of MM patient cells was similarly blocked within the same dose range. Our results therefore support clinical evaluation of AS703026, alone or in combination with other anti-MM agents, to improve patient outcome.
multiple myeloma (MM); MEK1/2 inhibitor; bone marrow stromal cells (BMSCs); novel kinase inhibitor therapy
The purpose of this study was to describe the nature of neglect in child welfare clients, to describe these experiences, to examine its typologies, and to understand how different types of neglect co-occurred with each other and with other types of maltreatment.
Case record abstraction was conducted on the child welfare case records of an urban, ethnically-diverse sample of youths (n = 303) identified as maltreated by a very large public child welfare agency. We utilized the Maltreatment Case Record Abstraction Instrument (MCRAI) which was based on the work of Barnett, Manly, and Cicchetti (1993) as modified by English and LONGSCAN (1997). Thirteen items of parental behavior deemed neglectful were coded and organized into 5 subtypes of neglect (care neglect, environmental neglect, medical neglect, educational neglect, supervisory neglect)
Neglect was present in 71.0% of the sample as compared to the 41.0% classified as neglected by CPS records. Neglect was accompanied by other types of maltreatment in 95% of the cases. Children who were neglected had more reports of maltreatment and experienced a greater number of different types of maltreatment than those who were maltreated, but not neglected. The most common type of neglect was supervisory neglect (72.5%) followed by environmental neglect (61.6%). With the exception of medical neglect, all types of neglect were significantly correlated with each other.
The abstraction resulted in rich data showing that under a one-word label of neglect, the nature of neglect that the youngsters actually experienced was quite diverse and heterogeneous in its phenomenology. Furthermore, neglect is pervasive for children in the child welfare system and official classifications underestimate its occurrence. Neglect does not happen in isolation; children who are reported as neglected are likely to experience other forms of maltreatment.
Official classifications should not be used in determining interventions for children and families. Interventions for neglected youngsters should be individualized to address the complexity of children's experiences.
Amyloidosis is a heterogeneous group of diseases in which misfolding of extracellular proteins is the pathogenic factor. Light chain amyloidosis (AL) is the most common form of amyloidosis, and the causative proteins in AL are the immunoglobulin light chains produced by clonal plasma cells. Hemorrhagic events, ranging from mild subcutaneous hemorrhage to life-threatening bleeding, account for a significant proportion of morbidities and mortality in AL patients. Deficiency of factor X from deposition into amyloid fibrils has been reported to be the most common acquired factor deficiency in AL. We herein report 2 patients with acquired factor X deficiency in AL. A 55-yr-old woman with AL had a prolonged prothrombin time (PT) and an activated partial thromboplastin time (aPTT) of 2.51 International Normalized Ratio (INR) and 75.1 sec, respectively, which were corrected on mixing with normal plasma. Factor X activity was markedly decreased at 5%. The other patient was a 67-yr-old man with AL with a PT of 1.63 INR and an aPTT of 50.3 sec, which were corrected on mixing with normal plasma. Factor X activity was decreased at 17%. Neither of the patients had apparent hemorrhagic manifestations. Identification of acquired factor deficiency and timely coagulation tests are needed in the diagnostic workup and management in AL.
Amyloidosis; Factor X deficiency; Korea
Diffuse large B-cell lymphoma (DLBCL) constitutes most primary central nervous system (CNS) lymphoma (PCNSL), whereas T-cell, low-grade and Burkitt’s lymphomas (BL) are rarely encountered. Due to the paucity of cases, little is known about the clinical features and treatment outcomes of PCNSL other than DLBCL. The objective of this study was to describe the clinical characteristics and outcomes for patients with PCNSL other than DLBCL. Fifteen patients, newly diagnosed with PCNSLs other than DLBCL between 2000 and 2010, were included. The male to female ratio was 0.67:1 with a median age of diagnosis of 31 years (range 18–59). Pathologic distributions were as follows: peripheral T-cell lymphoma (PTCL; n = 7), marginal zone B-cell lymphoma (MZBCL; n = 1), lymphoplasmacytic lymphoma (LPL; n = 2), Burkitt’s lymphoma (n = 1), other unspecified (T-cell lineage, n = 2; B-cell lineage, n = 2). Thirteen patients (87%) showed Eastern Cooperative Oncology Group performance score (ECOG PS) 1–2. The remaining two were one PTCL patient and one Burkitt’s lymphoma patient. Of the nine patients with T-cell lymphoma, five (56%) had multifocal lesions, and one (20%) with LPL of the five patients with B-cell lymphoma showed a single lesion. Leptomeningeal lymphomatosis was identified in two patients (one with Burkitt’s lymphoma and one with unspecified B-cell lymphoma). Two patients (22%) with T-cell lymphoma died 7.7 and 23.3 months later, respectively, due to disease progression, despite HD-MTX-based therapy. Six patients with T-cell lymphoma (6/9, 66.7%) and four patients with low-grade B-cell lymphoma (4/5, 80%) achieved complete response and have survived without relapse (Table 3). One patient with Burkitt’s lymphoma showed poor clinical features with ECOG PS 3, deep structure, multifocal, and leptomeningeal lymphomatosis, and died 7.6 months after the initiation of treatment. In comparison with previously reported DLBCLs (median OS 6.4 years, 95% CI 3.7–9.1 years), T-cell lymphoma showed equivocal or favorable clinical outcomes and low-grade B-cell lymphomas, such as MZBCL and LPL, had a good prognosis. However, primary CNS Burkitt’s lymphoma presented poor clinical outcomes and showed a comparatively aggressive clinical course. In conclusion, primary CNS lymphoma other than DLBCL occurred more in younger patients and showed a generally good prognosis, except for Burkitt’s lymphoma. Further research on treatment strategies for Burkitt’s lymphoma is needed.
Primary CNS lymphoma; Diffuse large B-cell lymphoma
The role of pre-transplant salvage chemotherapy has been controversial in relapsed acute leukemia.
We investigated post-transplant outcomes in 65 patients with acute leukemia treated with allogeneic hematopoietic cell transplantation (HCT) during first relapse or second remission.
The 5-year cumulative incidence of relapse (CIR) was 52.3%. Multivariate analysis for CIR revealed that patients with unfavorable cytogenetics and those not in remission at the time of HCT had a significantly high CIR (P = 0.031 and P = 0.031, respectively). Allogeneic HCT was performed in 14 patients after first relapse without salvage chemotherapy ("untreated relapse" group), 15 patients failed chemotherapy for reinduction of remission before HCT ("refractory relapse" group), and 36 patients attained second remission with salvage chemotherapy before HCT ("second remission" group). The 5-year CIR for patients in the untreated relapse group (57.1%) was higher than that for those in the second remission group (42.3%), but it was lower than that for patients in the refractory relapse group (66.7%). Among patients who underwent allogeneic HCT in relapse, those with bone marrow (BM) blasts ≤30% had a lower 5-year CIR than those in florid relapse (BM blasts >30%) (57.7% vs. 70.6%).
Our results do not support the role of salvage chemotherapy aimed at re-induction of remission before allogeneic HCT in patients with acute leukemia after first relapse. Patients with early relapse do not appear to benefit from salvage chemotherapy before HCT.
Allogeneic HCT; Acute leukemia; First relapse; Second remission
Fulminant Epstein–Barr virus (EBV+) T-cell lymphoma in immunocompetent elderly patients is rare and its character has not been well defined. This study analyzed the clinicopathological features of five elderly patients (group A: 50–84 years) and compared them with those of eight children and young adult patients with systemic T-cell lymphomas (group B: 10–34 years). Group A more commonly presented with generalized lymphadenopathy (n = 3) than did group B (n = 1). Chronic active EBV infection (n = 3) and hydroa vacciniforme-like eruptions (n = 1) were seen in group B, while group A showed no evidence of chronic EBV infection, but did show chronic hepatitis B or C virus infections (n = 3). The histological and immunophenotypical findings were similar. All patients died within 1 to 14 months of diagnosis. These findings suggest that EBV+ T-cell lymphoma in elderly patients is a unique disease with an underlying derangement of T-cell immunity and failure to eradicate infected virus. Additional factors related to senility may play a role in the disruption of homeostasis between the virus and the host’s immune system.
Epstein–Barr virus; Lymphoma; T-cell
We analyzed the efficacy and toxicity of a modified Cancer and Leukemia Group B (CALGB) 19802 regimen in adult acute lymphoblastic leukemia (ALL). From February 2002 to August 2005, 25 adults with untreated ALL were enrolled in the study. Compared to the original regimen, the modified CALGB 19802 regimen consisted of a 4-drug induction (cyclophosphamide, daunorubicin, vincristine, and prednisone) instead of a 5-drug induction (L-asparaginase was added to the previous regimen). This was followed by high-dose methotrexate (1,000 mg/m2×3 days) and cytarabine (2,000 mg/m2×4 days) for the consolidation cycles. High-dose systemic and intrathecal methotrexate was given for central nervous system prophylaxis. Twenty-three patients (92%) achieved a complete remission (CR), and two patients (8%) had refractory disease. With a median follow-up of 21.5 months, 10 patients (40%) were alive and continued to be in CR. The 3-yr probability of an event-free survival and the overall survival were 39.0% and 47.4%, respectively. Treatment related mortality and major grade 3 to 4 neurotoxicity occurred in 1 patient and 3 patients, respectively. The modified CALGB 19802 regimen demonstrated a high remission rate and a favorable survival rate.
Precursor Cell Lymphoblastic Leukemia-Lymphoma; Drug Therapy
Although high-dose intravenous immunoglobulin (IVIG) is generally considered a safe medication for various immune-mediated diseases, thrombotic events have been reported as a complication of the therapy. We report a case who developed thrombotic complications after receiving IVIG. A 56-yr-old woman with idiopathic thrombocytopenic purpura received IVIG at a dose of 400 mg/kg/day for five days. Three days after the administration of IVIG, the patient developed painful edema in the left leg. Lower extremity doppler ultrasound revealed deep vein thrombosis in the left leg. Chest computed tomography (CT) scan demonstrated a filling defect indicating thromboembolism of the right pulmonary artery. After three weeks of enoxaparin therapy, her symptoms and pulmonary embolism on CT improved. This case suggests clinicians should be cautious in the development of thromboembolism by administration of IVIG, especially in patients with thrombophilia.
Intravenous Immunoglobulins; Idiopathic Thrombocytopenic Purpura; Deep Vein Thrombosis; Pulmonary Embolism
Despite advanced effective prophylaxes, pulmonary complications still occur in a high proportion of all hematopoietic stem cell recipients, accounting for considerable morbidity and mortality. The aim of our study was to describe the causes, incidences and mortality rates secondary to pulmonary complications and risk factors of such complications following hematopoietic stem cell transplantation (HSCT). We reviewed the medical records of 287 patients who underwent either autologous or allogeneic HSCT for hematologic disorders from February 1996 to October 2003 at Samsung Medical Center (134 autografts, 153 allografts). The timing of pulmonary complications was divided into pre-engraftment, early and late period. The spectrum of pulmonary complications included infectious and non-infectious conditions. 73 of the 287 patients (25.4%) developed pulmonary complications. Among these patients, 40 (54.8%) and 29 (39.7%) had infectious and non-infectious conditions, respectively. The overall mortality rate from pulmonary complications was 28.8%. Allogeneic transplant, grade II-IV acute graft-versus-host disease (GVHD) and extensive chronic GVHD were the risk factors with statistical significance for pulmonary complications after HSCT. The mortality rates from pulmonary complications following HSCT were high, especially those of viral and fungal pneumonia, diffuse alveolar hemorrhage and idiopathic pneumonia syndrome.
Infection; Hematopoietic Stem Cell Transplantation; Graft vs. Host Disease
To verify the spectrum of CD99-expressing lymphoid malignancy, an immunohistochemical study for CD99 was carried out in 182 cases of non-Hodgkin's lymphoma, including 21 lymphoblastic lymphomas, 11 small lymphocytic lymphomas, 9 mantle cell lymphomas, 12 follicular lymphomas, 37 diffuse large B cell lymphomas, 18 Burkitt's lymphomas, 28 NK/T-cell lymphomas, 8 angioimmunoblastic T-cell lymphomas, 23 peripheral T-cell lymphomas, unspecified, and 15 systemic anaplastic large cell lymphomas. CD99 was positive in all T-lymphoblastic lymphomas and in 60% of B-lymphoblastic lymphomas. Majority of T and NK cell lymphomas were negative for CD99, except anaplastic large cell lymphomas (ALCLs). Eight of 15 cases (54%) of ALCLs reacted with anti CD99 antibody. Seven of 10 (70%) ALK positive ALCLs expressed CD99, whereas only 1 of 5 (20%) ALK negative ALCLs were positive. Of the mature B-cell lymphomas, 5.4% (2/37) of diffuse large B cell lymphomas and 11.1% (2/18) of Burkitt's lymphomas expressed CD99. In conclusion, CD99 is infrequently expressed in mature B and T cell lymphomas, except ALK-positive ALCL. High expression of CD99 in ALK-positive ALCL is unexpected finding and its biologic and clinical significances have yet to be clarified.
CD99 protein, human; Lymphoma, Non-Hodgkin; Lymphoma, Large-Cell, Ki-1
The association between a multiple myeloma and a secondary solid tumor is not well established. Some reports showed an increased risk of secondary solid neoplasms in multiple myeloma patients, but others have not. Three cases of the synchronous occurrence of multiple myelomas and solid tumors, namely, a small cell carcinoma of the lung, an adenocarcinoma of the colon and a squamous carcinoma of the pyriform sinus were experienced at our hospital. Therefore, herein is reported the clinical courses and treatment results. The stage of multiple myeloma was Durie-Salmon stage I in all of three cases; therefore, the solid tumors were treated as a primary target because the prognosis of early stage multiple myeloma is generally better than that of advanced solid tumor, while a smoldering or stage I myeloma do not need primary therapy until progression of the multiple myeloma. Two patients died of their solid tumors, but one patient is alive.
Multiple myeloma; Synchronous neoplasm; Second neoplasm
Herein, a case of solitary, unilateral renal metastasis in a patient with curatively resected thoracic esophageal carcinoma, who achieved a pathological complete remission after neoadjuvant concurrent chemoradiotherapy, is reported. The kidney is the 4th or 5th most common visceral metastasis site of a primary esophageal carcinoma. More than 50% of renal metastases typically show bilateral involvement. Solitary, unilateral renal metastasis is extremely rare. Renal metastases from a primary esophageal carcinoma are usually latent and its diagnosis is very unusual in a live patient. The solitary renal metastasis in this case was not accompanied by metastases to other sites. The value of a nephrectomy in solitary renal metastasis of esophageal cancer is not known due to the rarity of such cases. A nephrectomy could be justified in limited situations, such as with uncertainty of histological diagnosis, severe life-threatening hematuria, which cannot be controlled by embolization, or solitary renal metastasis with a long disease-free interval.
Esophageal carcinoma; Metastasis; Kidney
Major ABO incompatibility may be potentially associated with immediate or delayed hemolysis and delayed onset of erythropoiesis in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). To determine if hemolysis can be prevented by the inhibition of graft erythropoiesis, we performed hypertransfusion and assessed red cell transfusion requirement and independence. Between October 1995 and December 2001, 28 consecutive patients receiving major ABO incompatible HSCT at Samsung Medical Center were hypertransfused to maintain their hemoglobin levels at 15 g/dL or more. We retrospectively compared the outcomes of these patients with those of 47 patients at Asan Medical Center whose target hemoglobin levels were 10 g/dL. Reticulocyte engraftment was significantly delayed in hypertransfused group (51 days vs. 23 days; p=.001). There was no significant difference in the total amount of red cells transfused within 90 days post-HSCT (25 units vs. 26 units; p=.631). No significant difference in the time to red cell transfusion independence was observed between the two groups (63 days vs. 56 days; p=.165). In conclusion, we failed to improve red cell transfusion requirement and independence in major ABO incompatible HSCT with hypertransfusion.
Blood Transfusion; Blood Group Incompatibility; Hemolysis; Hematopoietic Stem Cell Transplantation