Identification and overcoming rituximab resistance in diffuse large B-cell lymphoma using next-generation sequencing

Background/Aims@#Although rituximab, an antiCD20 monoclonal antibody, has dramatically improved the clinical outcomes of diffuse large B-cell lymphoma, rituximab resistance remains a challenge. @*Methods@#We developed a rituximab-resistant cell line (RRCL) by sequential exposure to gradually increasing concentrations of rituximab in a rituximab-sensitive cell line (RSCL). When the same dose of rituximab was administered, RRCL showed a smaller decrease in cell viability and apoptosis than RSCL. To determine the differences in gene expression between RSCL and RRCL, we performed next-generation sequencing. @*Results@#In total, 1,879 differentially expressed genes were identified, and in the over-representation analysis of Consensus-PathDB, mitogen-activated protein kinase (MAPK) signaling pathway showed statistical significance. MAPK13, which encodes the p38δ protein, was expressed more than four-fold in RRCL. Western blot analysis revealed that phosphop38 expression mainwas increased in RRCL, and when p38 inhibitor was administered, phosphop38 expression was significantly decreased. Therefore, we hypothesized that p38 MAPK activation was associated with rituximab resistance. Previous studies have suggested that p38 is associated with NF-κB activation. Deferasirox has been reported to inhibit NF-κB activity and suppress phosphorylation of the MAPK pathway. Furthermore, it also has cytotoxic effects on various cancers and synergistic effects in overcoming drug resistance. In this study, we confirmed that deferasirox induced dose-dependent cytotoxicity in both RSCL and RRCL, and the combination of deferasirox and rituximab showed a synergistic effect in RRCL at all combination concentrations. @*Conclusions@#We suggest that p38 MAPK, especially p38δ, activation is associated with rituximab resistance, and deferasirox may be a candidate to overcome rituximab resistance.

Long-Term Efficacy and Safety of Eculizumab in Patients With Paroxysmal Nocturnal Hemoglobinuria and High Disease Burden: Real-World Data From Korea

Background@#Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by uncontrolled terminal complement activation. Eculizumab, a monoclonal antibody C5 inhibitor was introduced in Korea in 2009 and has been the standard treatment option for PNH. @*Methods@#This study assessed the long-term efficacy/safety of eculizumab in PNH using real-world data from the Korean Health Insurance Review and Assessment Service. Eighty patients who initiated eculizumab from 2009–2020 were enrolled. @*Results@#At eculizumab initiation, the median age was 51.5 years, lactate dehydrogenase (LDH) 6.8 × upper limit of normal, and granulocyte clone size 93.0%. All patients had at least one PNH-related complication before eculizumab initiation, including renal failure (n = 36), smooth muscle spasm (n = 24), thromboembolism (n = 20), and pulmonary hypertension (n = 15). The median (range) duration of eculizumab treatment was 52.7 (1.0, 127.3) months (338.6 total treated patient-years). Despite high disease activity in the study population before treatment initiation, overall survival was 96.2% and LDH levels were stabilized in most patients during treatment. PNH-related complications at treatment initiation were resolved in 44.4% of patients with renal failure, 95.8% with smooth muscle spasm, 70.0% with thromboembolism, and 26.7% with pulmonary hypertension. Extravascular hemolysis occurred in 28.8% of patients (n = 23; 0.09 per patient-year) and breakthrough hemolysis in 18.8% (n = 15; 0.06 per patient-year). No treatment discontinuation cases related to eculizumab were observed. @*Conclusion@#These data provided evidence for the long-term efficacy and safety of eculizumab in Korean PNH patients with high disease burdens.

Intensified First Cycle of Rituximab Plus Eight Cycles of Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone with Rituximab Chemotherapy for Advanced-Stage or Bulky Diffuse Large B-Cell Lymphoma: A Multicenter Phase II Consortium for Improving Survival of Lymphoma (CISL) Study / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#This phase II, open-label, multicenter study aimed to investigate the efficacy and safety of a rituximab intensification for the 1st cycle with every 21-day of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP-21) among patients with previously untreated advanced-stage or bulky diffuse large B-cell lymphoma (DLBCL). @*Materials and Methods@#Ninety-two patients with stage III/IV or bulky DLBCL from 21 institutions were administered 8 cycles of R-CHOP-21 with an additional one dose of rituximab intensification on day 0 of the 1st cycle (RR-CHOP). The primary endpoint was a complete response (CR) rate after 3 cycles of chemotherapy. @*Results@#Among the 92 DLBCL patients assessed herein, the response rate after 3 cycles of chemotherapy was 88.0% (38.0% CR+50.0% partial response [PR]). After the completion of 8 cycles of chemotherapy, the overall response rate was observed for 68.4% (58.7% CR+9.8% PR). The 3-year progression-free survival rate was 64.0%, and the 3-year overall survival rate was 70.4%. Febrile neutropenia was one of the most frequent grade 3 adverse events (40.0%) and 5 treatment-related deaths occurred. Compared with the clinical outcomes of patients who received R-CHOP chemotherapy as a historical control, the interim CR rate was higher in male patients with RR-CHOP (20.5% vs. 48.8%, p=0.016). @*Conclusion@#Rituximab intensification on days 0 to the 1st cycle of the standard 8 cycles R-CHOP-21 for advanced DLBCL yielded favorable response rates after the 3 cycles of chemotherapy and acceptable toxicities, especially for male patients. ClinicalTrials.gov ID: NCT01054781.

Composite follicular lymphoma and classic Hodgkin lymphoma

Composite lymphoma is very rare and a combination of Hodgkin lymphoma and non-Hodgkin lymphoma and even histiocytic tumors can occur. Because of the unfamiliarity, not only can this cause diagnostic problems, but can also affect treatment plan. We report a case of composite lymphoma in a 40-year-old male. Initial biopsy showed a composite lymphoma of follicular lymphoma grade 1 and classic Hodgkin lymphoma. After chemotherapy, another lymph node was taken because of disease progression, which revealed follicular lymphoma, grade 3a without Hodgkin lymphoma component.

How myeloproliferative neoplasms patients’ experience and expectations differ from physicians’: the international MPN Landmark survey

Background/Aims@#Recent advances in the understanding of the pathophysiology of myeloproliferative neoplasms (MPN) were not paralleled with advances in treatment options; thus many questions regarding optimal MPN management remain unanswered. Here, we report the results of descriptive survey study of Korean MPN patients and their attending physicians. @*Methods@#A total of 105 Korean patients (myelofibrosis [MF], 39; polycythemia vera [PV], 25; essential thrombocythemia [ET], 41) and 30 physicians completed the Landmark Health Survey, then data from the survey were analyzed. @*Results@#Among the MPN-Symptom Assessment Form symptoms, the most severe symptom reported was ‘fatigue or tiredness’ in MF and ET patients and ‘itching’ in PV patients. The majority of the patients agreed that MPN reduced their quality of life (QoL). Interestingly, physicians gave higher scores regarding the impact of MPN on patient’s daily and social life compared to patients themselves. For patients, the most important treatment goal was symptom improvement regardless of MPN subtype, while for physicians the highest priority for treatment was better QoL regardless of MPN subtype. Generally, both patients and physicians were satisfied with the overall treatment/management of MPN and communications. However, many patients felt there was not enough time during the appointment for discussion, while many physicians felt they lacked effective drugs to offer to their patients. @*Conclusions@#Our study suggests there are room for better-standardized monitoring of symptoms and treatment options and those continuous efforts to bridge the gap between patients and physicians are necessary for better care of MPN patients.

Safety and efficacy of nilotinib in adult patients with chronic myeloid leukemia: a post-marketing surveillance study in Korea

Background@#Nilotinib is a tyrosine kinase inhibitor approved by the Ministry of Food and Drug Safety for frontline and 2nd line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML). This study aimed to confirm the safety and efficacy of nilotinib in routine clinical practice within South Korea. @*Methods@#An open-label, multicenter, single-arm, 12-week observational post-marketing surveillance (PMS) study was conducted on 669 Korean adult patients with Ph + CML from December 24, 2010, to December 23, 2016. The patients received nilotinib treatment in routine clinical practice settings. Safety was evaluated by all types of adverse events (AEs) during the study period, and efficacy was evaluated by the complete hematological response (CHR) and cytogenetic response. @*Results@#During the study period, AEs occurred in 61.3% (410 patients, 973 events), adverse drug reactions (ADRs) in 40.5% (271/669 patients, 559 events), serious AEs in 4.5% (30 patients, 37 events), and serious ADRs in 0.7% (5 patients, 8 events). Furthermore, unexpected AEs occurred at a rate of 6.9% (46 patients, 55 events) and unexpected ADRs at 1.2% (8 patients, 8 events). As for the efficacy results, CHR was achieved in 89.5% (442/494 patients), and minor cytogenetic response or major cytogenetic response was achieved in 85.8% (139/162 patients). @*Conclusion@#This PMS study shows consistent results in terms of safety and efficacy compared with previous studies. Nilotinib was well tolerated and efficacious in adult Korean patients with Ph + CML in routine clinical practice settings.

Hepatic sinusoidal obstruction syndrome/veno-occlusive disease after hematopoietic cell transplantation: historical and current considerations in Korea

Hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a rare but severe complication of hematopoietic cell transplantation (HCT) showing high mortality. Multiple risk factors for SOS/VOD were identified, but it is often confused with other hepatic complications due to nonspecific clinical features. Therefore, diagnostic and severity criteria have been revised several times. The European Society of Blood and Marrow Transplantation suggested a new guideline that excludes the standard duration of development within 21 days, emphasizes late-onset SOS/VOD, and suggests the importance of Doppler ultrasonography. The severity criteria were further subdivided for guidance to begin active treatment using defibrotide which was approved in Korea since 2016. In a phase 3 trial, defibrotide had superior 100-day survival, compared to best available treatments (38.2% vs. 25.0%). Although several studies of SOS/VOD in Korean patients have been performed after the implementation of HCT, most involved small number of pediatric patients. Recently, the Korean Society of Blood and Marrow Transplantation investigated the incidence of SOS/VOD in the Korean population, and several influential studies of adult patients were published. Here, we summarize recent issues regarding the mechanism, diagnosis, severity criteria, prevention, and treatments of SOS/VOD in Korean patients, as well as recent analyses of nationwide incidence.

The effect of the response to the coronavirus disease pandemic on treatment outcomes in patients with lymphoma and multiple myeloma

Background/Aims@#Relatively little data are available on how the response to the coronavirus disease 2019 (COVID-19) pandemic has affected treatment outcomes in patients receiving chemotherapy for lymphoma or multiple myeloma. We aimed to determine the effect of COVID-19 countermeasures on treatment outcomes in this patient population. @*Methods@#We retrospectively analyzed data on patients treated for lymphoma or multiple myeloma in two tertiary hospitals in Seoul. Patients were divided into two groups: group 1 included patients who received chemotherapy between September and December 2019 (the control period), and group 2 included patients who received chemotherapy between September and December 2020 (the study period). Countermeasures to COVID-19 were applied to the patients in group 2. The countermeasures implemented included mask wearing and regular handwashing at home and in hospital; COVID-19 risk assessments on all hospital visitors; and pre-emptive COVID-19 screening for all newly hospitalized patients and their resident guardians. @*Results@#No differences in treatment outcomes, including treatment response, incidence and duration of neutropenia or neutropenic fever, delays in chemotherapy, or number of deaths during chemotherapy, were observed between the g roups. None of the patients in group 2 tested positive for COVID-19, and there were no COVID-19-related deaths during the study period. @*Conclusions@#Countermeasures to COVID-19 did not affect treatment outcomes in patients receiving chemotherapy for lymphoma or multiple myeloma. Data on the effect of countermeasures to COVID-19 on treatment outcomes should continue to be analyzed to ensure that treatment outcomes are not adversely affected.

Metformin enhances the cytotoxic effect of nilotinib and overcomes nilotinib resistance in chronic myeloid leukemia cells

Nilotinib is used for treating patients with imatinib-sensitive or -resistant chronic myeloid leukemia (CML); however, nilotinib-resistant cases have been observed in recent years. In addition, a considerable number of patients receiving nilotinib developed diabetes. Metformin is a front-line drug for the treatment of type 2 diabetes, and several studies have shown that diabetes patients treated with metformin have reduced incidence of cancer. This study aimed to define the effect of metformin on CML cells to determine whether metformin overcomes nilotinib resistance, and to identify novel targets for the treatment of nilotinib resistance. Methods: We observed the effects of metformin and nilotinib on K562 and KU812 human CML cell lines. Nilotinib-resistant CML cell lines were generated by exposing cells to gradually increasing doses of nilotinib. Then, we investigated the driving force that makes resistance to nilotinib and the effect of metformin on the driving force. Results: Sub-toxic doses of metformin enhanced nilotinib efficacy by reducing Bcl-xL expression, which induces apoptosis in CML cells. Next, we generated nilotinib-resistant K562 and KU812 cell lines that overexpressed the c-Jun N-terminal kinase (JNK) gene. JNK silencing by a JNK inhibitor restored sensitivity to nilotinib. Furthermore, metformin was effective in decreasing phosphorylated JNK levels, restoring nilotinib sensitivity. Combined treatment with nilotinib and metformin was more effective than combined treatment with nilotinib and a JNK inhibitor in terms of cell proliferation inhibition. Conclusions: This study suggested that combination therapy with metformin and nilotinib may have clinical benefits of enhancing antileukemia efficacy and overcoming resistance to nilotinib.

The 2020 revision of the guidelines for the management of myeloproliferative neoplasms

In 2016, the World Health Organization revised the diagnostic criteria for myeloproliferative neoplasms (MPNs) based on the discovery of disease-driving genetic aberrations and extensive analysis of the clinical characteristics of patients with MPNs. Recent studies have suggested that additional somatic mutations have a clinical impact on the prognosis of patients harboring these genetic abnormalities. Treatment strategies have also advanced with the introduction of JAK inhibitors, one of which has been approved for the treatment of patients with myelofibrosis and those with hydroxyurea-resistant or intolerant polycythemia vera. Recently developed drugs aim to elicit hematologic responses, as well as symptomatic and molecular responses, and the response criteria were refined accordingly. Based on these changes, we have revised the guidelines and present the diagnosis, treatment, and risk stratification of MPNs encountered in Korea.

The role of platelet function analyzer-200 in predicting perioperative bleeding risk

Background/Aims@#Various preoperative screening tests, such as platelet count, prothrombin time, activated partial thromboplastin time, and bleeding time, have been widely used to evaluate the risk of bleeding during surgery. Use of platelet function analyzer (PFA)-100/200 for assessing platelet function instead of bleeding time is increasing. However, its role in predicting the perioperative risk of bleeding remains controversial. @*Methods@#Data of 703 patients who underwent surgery under general anesthesia were retrospectively analyzed. Preoperative platelet function was measured using PFA-200 system and the association with intraoperative bleeding was assessed. Additionally, other variables that could affect PFA-200 results were assessed by logistic regression analysis. @*Results@#Collagen/epinephrine (COL/EPI) test was prolonged in 199/703 (28.3%) patients (EPI group), while 99/212 (46.7%) patients showed COL/adenosine diphosphate test abnormalities. Bleeding over 300 mL during surgery occurred in 14.3% and 20.1% of patients in the normal and EPI groups, respectively (p = 0.058). In addition, red blood cell transfusion within 72 hours after surgery rate was significantly higher in the EPI group than in the normal group (31.7% vs. 23.4%,p= 0.024). In multivariate logistic analysis, prolongation closure time with COL/EPI (p = 0.068) was marginally associated with risk of bleeding during surgery. Furthermore, PFA-200 results were influenced by various factors, such as nonsteroidalanti-inflammatory drug use, blood group, hematocrit, and time of blood collection. @*Conclusions@#Preoperative PFA-200 test may be helpful in predicting the risk of perioperative bleeding. However, its results should be carefully interpreted becausethey are affected by several factors.

Immature platelet fraction based diagnostic predictive scoring model for immune thrombocytopenia

Background/Aims@#The diagnosis of immune thrombocytopenia (ITP) is based on clinical manifestations and there is no gold standard. Thus, even hematologic malignancy is sometimes misdiagnosed as ITP and adequate treatment is delayed. Therefore, novel diagnostic parameters are needed to distinguish ITP from other causes of thrombocytopenia. Immature platelet fraction (IPF) has been proposed as one of new parameters. In this study, we assessed the usefulness of IPF and developed a diagnostic predictive scoring model for ITP. @*Methods@#We retrospectively studied 568 patients with thrombocytopenia. Blood samples were collected and IPF quantified using a fully-automated hematology analyzer. We also estimated other variables that could affect thrombocytopenia by logistic regression analysis. @*Results@#The median IPF was significantly higher in the ITP group than in the non-ITP group (8.7% vs. 5.1%). The optimal cut-off value of IPF for differentiating ITP was 7.0%. We evaluated other laboratory variables via logistic regression analysis. IPF, hemoglobin, lactate dehydrogenase (LDH), and ferritin were statistically significant and comprised a diagnostic predictive scoring model. Our model gave points to each of variables: 1 to high hemoglobin (> 12 g/dL), low ferritin (≤ 177 ng/ mL), normal LDH (≤ upper limit of normal) and IPF ≥ 7 and < 10, 2 to IPF ≥ 10. The final score was obtained by summing the points. We defined that ITP could be predicted in patients with more than 3 points. @*Conclusions@#IPF could be a useful parameter to distinguish ITP from other causes of thrombocytopenia. We developed the predictive scoring model. This model could predict ITP with high probability.

Recent insights regarding the molecular basis of myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal disorders characterized by the overproduction of mature blood cells that have an increased risk of thrombosis and progression to acute myeloid leukemia. Next-generation sequencing studies have provided key insights regarding the molecular mechanisms of MPNs. MPN driver mutations in genes associated with the JAK-STAT pathway include JAK2 V617F, JAK2 exon 12 mutations and mutations in MPL, CALR, and CSF3R. Cooperating driver genes are also frequently detected and also mutated in other myeloid neoplasms; these driver genes are involved in epigenetic methylation, messenger RNA splicing, transcription regulation, and signal transduction. In addition, other genetic factors such as germline predisposition, order of mutation acquisition, and variant allele frequency also influence disease initiation and progression. This review summarizes the current understanding of the genetic basis of MPN, and demonstrates how molecular pathophysiology can improve both our understanding of MPN heterogeneity and clinical practice.

Modified dose of melphalan-prednisone in multiple myeloma patients receiving bortezomib plus melphalan-prednisone treatment

BACKGROUND/AIMS@#Bortezomib plus melphalan-prednisone (VMP) is a standard treatment for multiple myeloma, particularly for patients who are ineligible for high-dose therapy. However, early discontinuation or treatment modification is often needed owing to adverse events. The aim of this study was to investigate the clinical outcomes of modifying the dose of melphalan-prednisone (MP) in patients receiving VMP.@*METHODS@#We examined 67 patients who received a modified dose of MP, and 38 patients who received the regularly planned dose of MP. We then analyzed clinical differences between the groups.@*RESULTS@#Although there was no difference in the proportion of discontinuation due to adverse events between dose groups, more patients in the planned-dose group experienced earlier discontinuation in general. The overall response rate (ORR) was 81.0% and complete response (CR) rate was 30.5%. After a median 15.7 months of follow-up, the median progression-free survival (PFS) and overall survival (OS) were 25.0 and 47.8 months, respectively. There was no significant difference in the ORR, CR, PFS, and OS of the two dose groups. A median of four cycles were delivered, and the median cumulative bortezomib dose was 41.6 mg/m². The median PFS in patients with doses ≥ 41.6 mg/m² was longer than that in patients with doses < 41.6 mg/m² (35.1 months vs. 9.6 months). However, when MP was < 50% of the planned dose, PFS and OS were poor.@*CONCLUSIONS@#Modifying the dose of MP might be a feasible and effective therapeutic approach for multiple myeloma patients receiving VMP treatment.

Analysis of Overall Survival According to Bone Marrow Aspiration Results in Non-Hodgkin's Lymphoma Patients / 대한내과학회지

BACKGROUND/AIMS: The staging work-up for patients with non-Hodgkin's lymphoma includes bone marrow aspiration and biopsy. Consistent results of both procedures can clarify the diagnosis. However, no clear guidelines have been established regarding positive results for bone marrow aspiration alone. The aim of this study was, therefore, to analyze the overall survival (OS) for the clinical diagnoses of these patients using morphological methods. METHODS: We performed a retrospective analysis of patients who were consecutively enrolled in the Korea University Lymphoma Registry from 1991 to 2016. OS was compared according to the bone marrow group: without bone marrow involvement (BMA−/BMBx−), with positive results for aspiration and negative results for biopsy (BMA+/BMBx−), and with bone marrow involvement in biopsy (BMBx+). OS was assessed using the Kaplan-Meier method and multivariate analysis. RESULTS: Of 1,735 patients, 1,326 were analyzed and 409 were excluded. In the Kaplan-Meier survival analysis, OS was significantly worse for patients in the BMBx+ group compared with those in the BMA−/BMBx− group (p < 0.001). However, there was no significant difference in OS between patients in the BMA+/BMBx− group and those in other groups (vs. BMA−/BMBx−, p = 0.163; BMBx+, p = 0.292). In multivariate analysis, by adjusting survival-related variables, the BMA+/BMBx− group showed marginal significance compared to the BMA−/BMBx− group (p = 0.081), and showed significance in the subgroup of indolent non-Hodgkin's lymphoma patients (p = 0.003). CONCLUSIONS: This study suggested that even if there are positive results in bone marrow aspiration alone in patients with non-Hodgkin lymphoma, attention to patient characteristics, involving significance as a poor prognosis for OS, is required.

Analysis of Overall Survival According to Bone Marrow Aspiration Results in Non-Hodgkin's Lymphoma Patients / 대한내과학회지

BACKGROUND/AIMS@#The staging work-up for patients with non-Hodgkin's lymphoma includes bone marrow aspiration and biopsy. Consistent results of both procedures can clarify the diagnosis. However, no clear guidelines have been established regarding positive results for bone marrow aspiration alone. The aim of this study was, therefore, to analyze the overall survival (OS) for the clinical diagnoses of these patients using morphological methods.@*METHODS@#We performed a retrospective analysis of patients who were consecutively enrolled in the Korea University Lymphoma Registry from 1991 to 2016. OS was compared according to the bone marrow group: without bone marrow involvement (BMA−/BMBx−), with positive results for aspiration and negative results for biopsy (BMA+/BMBx−), and with bone marrow involvement in biopsy (BMBx+). OS was assessed using the Kaplan-Meier method and multivariate analysis.@*RESULTS@#Of 1,735 patients, 1,326 were analyzed and 409 were excluded. In the Kaplan-Meier survival analysis, OS was significantly worse for patients in the BMBx+ group compared with those in the BMA−/BMBx− group (p < 0.001). However, there was no significant difference in OS between patients in the BMA+/BMBx− group and those in other groups (vs. BMA−/BMBx−, p = 0.163; BMBx+, p = 0.292). In multivariate analysis, by adjusting survival-related variables, the BMA+/BMBx− group showed marginal significance compared to the BMA−/BMBx− group (p = 0.081), and showed significance in the subgroup of indolent non-Hodgkin's lymphoma patients (p = 0.003).@*CONCLUSIONS@#This study suggested that even if there are positive results in bone marrow aspiration alone in patients with non-Hodgkin lymphoma, attention to patient characteristics, involving significance as a poor prognosis for OS, is required.

Combination Treatment of Stereotactic Body Radiation Therapy and Immature Dendritic Cell Vaccination for Augmentation of Local and Systemic Effects / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The purpose of this study was to investigate the efficacy of stereotactic body radiation therapy (SBRT) as a tumor-associated antigen (TAA) presentation method for dendritic cell (DC) sensitization and evaluate its effect in combination with immunotherapy using an intratumoral injection of immature DCs (iDCs). MATERIALS AND METHODS: CT-26 colon carcinoma cell was used as a cancer cell line. Annexin V staining and phagocytosis assays were performed to determine the appropriate radiation dose and incubation time to generate TAAs. BALB/c mice were used for in vivo experiments. Cancer cells were injected into the right legs and left flanks to generate primary and metastatic tumors, respectively. The mice were subjected to radiation therapy (RT) alone, intradermal injection of electroporated DCs alone, or RT in combination with iDC intratumoral injection (RT/iDC). Tumor growth measurement and survival rate analysis were performed. Enzyme-linked immunospot and cytotoxicity assays were performed to observe the effect of different treatments on the immune system. RESULTS: Annexin V staining and phagocytosis assays showed that 15 Gy radiation dose and 48 hours of incubation was appropriate for subsequent experiments. Maximum DC sensitization and T-cell stimulation was observed with RT as compared to other TAA preparation methods. In vivo assays revealed statistically significant delay in the growth of both primary and metastatic tumors in the RT/iDC group. The overall survival rate was the highest in the RT/iDC group. CONCLUSION: The combination of SBRT and iDC vaccination may enhance treatment effects. Clinical trials and further studies are warranted in the future.

Multicenter Planning Comparison of Stereotactic Body Radiotherapy for Hepatocellular Carcinoma with Major Portal Vein Tumor Thrombosis (KROG 16-17)

BACKGROUND/AIMS: To evaluate the technical feasibility of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC) with the major portal vein tumor thrombosis (PVTT). METHODS: Ten institutions affiliated with the Korean Stereotactic Radiosurgery Group were provided the contours of four cases: the first case was the first branch PVTT with sufficient normal liver volume (NLV), the second was the first branch PVTT with insufficient NLV, the third was the main trunk PVTT at confluence level, and the fourth was the main trunk PVTT with entire length. The institutions were asked to make SBRT plans according to their current treatment protocols and to complete facility questionnaires. RESULTS: Based on institutional protocols, SBRT was feasible in nine institutions for the first case (32–60 Gy in 3–5 fractions), in eight institutions for the second case (32–50 Gy in 3–5 fractions), in seven institutions for the third case (35–60 Gy in 3–5 fractions), and in four institutions for the fourth case (35–42 Gy in 4–5 fractions). The other institutions recommended hypo- or conventional fractionation due to insufficient NLV or gastrointestinal organ proximity. With analysis of the SBRT dose to the central hepatobiliary tract, the major PVTT could theoretically be associated with a high risk of hepatobiliary toxicity. CONCLUSIONS: Although SBRT is a technically feasible option for HCC with the major PVTT, there was a variability among the participating institutions. Therefore, further studies will be necessary to standardize the practice of SBRT for the major PVTT.

Loeffler endocarditis in chronic eosinophilic leukemia with FIP1L1/PDGFRA rearrangement: full recovery with low dose imatinib

No abstract available.

Myeloma prognostic index at diagnosis might be a prognostic marker in patients newly diagnosed with multiple myeloma

BACKGROUND/AIMS: The aims of this study were to identify the value of inflammatory markers as pretreatment prognostic factors for patients with multiple myeloma (MM) and to estimate the value of a prognostic index including these markers at diagnosis. METHODS: A total of 273 newly diagnosed MM patients undergoing active treatment were analyzed in this study. The prognostic values for survival of the pretreatment inflammatory markers were investigated. A myeloma prognostic index (MPI) was derived using prognostic factors determined to be independently significant on multivariate analysis. RESULTS: A high pretreatment neutrophil-lymphocyte ratio (NLR), low platelet count, and high C-reactive protein (CRP) level had independently unfavorable significance for overall survival (OS). The MPI was derived based on these factors. Per the MPI, 1 point each was assigned to high NLR, low platelet count, and high CRP. Risk categories were stratified into low- (score 0), intermediate- (score 1), and high-risk (score 2 or 3) groups. The MPI demonstrated independent statistical significance for OS on multivariate analysis ([intermediate: hazard ratio (HR), 1.91; 95% confidence interval (CI), 1.12 to 3.24] and [high: HR, 3.37; 95% CI, 2.00 to 5.69]; p < 0.001). Moreover, this significance could be observed regardless of age, renal function, and exposure to novel agents. In addition, the International Staging System risk group could be further significantly stratified using the MPI. CONCLUSIONS: The MPI, consisting of pretreatment inflammatory markers, NLR, platelet count, and CRP, might be effective in predicting the survival of newly diagnosed MM patients undergoing active treatment.