Assessment of Bone Marrow Involvement in B-Cell non-Hodgkin Lymphoma Using Immunoglobulin Gene Rearrangement Analysis with Next-Generation Sequencing.

BACKGROUND: Assessment of bone marrow involvement (BMI) in non-Hodgkin lymphoma (NHL) is crucial for determining patient prognosis and treatment strategy. We assessed the prognostic value of next-generation sequencing (NGS)-based immunoglobulin (Ig) gene clonality analysis as an ancillary test for BMI evaluation in NHL. METHODS: A retrospective cohort of 124 patients newly diagnosed with B-cell NHL between 2019 and 2022 was included. NGS-based Ig clonality analysis was conducted using LymphoTrak IGH FR1 Assay and IGK Assay (Invivoscribe Technologies, San Diego, CA, USA) on BM aspirate samples, and the results were compared with those of histopathological BMI (hBMI). RESULTS: Among the 124 patients, hBMI was detected in 16.9% (n = 21). The overall agreement of BMI between Ig clonality analyses and histopathological analysis for IGH, IGK, and either IGH or IGK was 86.3%, 92.7%, and 90.3%. The highest positive percent agreement was observed with clonal rearrangements of either IGH or IGK gene (90.5%), while the highest negative percent agreement was observed with clonal rearrangement of IGK gene (96.1%). For the prediction of hBMI, positive prediction value ranged between 59.1% and 80.0% and the negative prediction value ranged between 91.3% and 97.9%. CONCLUSION: NGS-based clonality analysis is an analytic platform with a substantial overall agreement with histopathological analysis. Assessment of both IGH and IGK genes for the clonal rearrangement analysis could be considered for the optimal diagnostic performance of BMI detection in B-cell NHL.

Differences in Clinical Outcomes Between Hydroxyurea-Resistant and -Intolerant Polycythemia Vera Patients.

BACKGROUND: Previous studies have suggested that patients with polycythemia vera (PV) who exhibit hydroxyurea-resistance (HU-R) and -intolerance (HU-I) may have distinct characteristics and clinical outcomes. However, to date, no studies have reported a comparison between these two groups or assessed prognostic factors in these patients. METHODS: The objective of this study was to evaluate clinical outcomes and identify prognostic factors among PV patients with HU-R or HU-I. We conducted a review of PV patients who received frontline treatment with HU from nine centers and identified 90 patients with HU-R or HU-I. RESULTS: The cumulative incidence of thrombosis after 7 years of HU-R/I was 21.4%, and the incidence of disease progression was 22.5%. Comparing the HU-R and HU-I groups, the HU-R group had a significantly higher rate of disease progression (36.7% vs. 0.56%, P = 0.009), while there was no significant difference in thrombosis incidence (19.0% vs. 22.9%, P = 0.463). Multivariate analysis revealed that HU-R was an independent prognostic factor for progression-free survival (hazard ratio, 6.27, 95% confidence interval, 1.83-21.47, P = 0.003). Additionally, higher lactate dehydrogenase levels, multiple cardiovascular risk factors, and prior thrombosis were identified as unfavorable predictors of overall survival. CONCLUSION: These findings suggest that patients with HU-R face a higher risk of hematological transformation, but have a comparable risk of thrombosis to patients with HU intolerance. These distinctions should guide decisions on second-line treatment options and clinical trials involving these patients.

Prognostic outcomes of cytomegalovirus reactivation after autologous stem cell transplantation.

Background: Cytomegalovirus (CMV) reactivation is a common complication in patients undergoing allogeneic stem cell transplantation. However, the incidence of CMV reactivation is low after autologous stem cell transplantation (auto-SCT), and the prognostic value of CMV reactivation remains controversial. Moreover, reports on late CMV reactivation after auto-SCT are limited. We aimed to analyze the association between CMV reactivation and survival outcomes and develop a predictive model for late CMV reactivation in patients undergoing auto-SCT. Methods: Data of 201 patients who underwent SCT at the Korea University Medical Center from 2007 to 2018 were collected. We analyzed prognostic factors for survival outcomes after auto-SCT and risk factors for late CMV reactivation using a receiver operating characteristic curve. Then, we developed a predictive risk model for late CMV reactivation based on results of the risk factor analysis. Results: Early CMV reactivation was significantly associated with better overall survival (OS) (hazard ratio [HR], 0.329; P = 0.045) in patients with multiple myeloma; however, no significant differences were observed in patients with lymphoma. For late CMV reactivation, a serum lactate dehydrogenase level greater than the upper limit of normal (HR, 2.251; P = 0.027) and late CMV reactivation (HR, 2.964; P = 0.047) were independent risk factors for poor OS, while lymphoma diagnosis (vs. multiple myeloma; HR, 0.389; P = 0.016) was an independent risk factor for good OS. In risk factor analysis for late CMV reactivation, T-cell lymphoma diagnosis (odds ratio [OR], 8.499; P = 0.029), ≥ two prior chemotherapies (OR, 8.995; P = 0.027), failure to achieve complete response (CR) after transplantation (OR, 7.124; P = 0.031), and early CMV reactivation (OR, 12.853; P = 0.007) were significantly associated with late CMV reactivation. To develop the predictive risk model for late CMV reactivation, a score (1 to 1.5) was assigned for each of the above-mentioned variables. The optimal cutoff value (1.75 points) was calculated using the receiver operating characteristic curve. The predictive risk model showed good discrimination, with an area under the curve of 0.872 (standard error, 0.062; P < 0.001). Conclusions: Late CMV reactivation was an independent risk factor for inferior OS, whereas early CMV reactivation was associated with better survival in patients with multiple myeloma. This risk prediction model could be helpful in identifying high-risk patients who require monitoring for late CMV reactivation and potentially benefit from prophylactic or preemptive therapy.

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.

Psychiatric comorbidities and quality of life in breast cancer patients undergoing radiation treatment: Risk and protective factors.

OBJECTIVE: The primary goal was to evaluate the prevalence of psychiatric comorbidities and changes in psychological distress levels among breast cancer patients receiving radiotherapy (RT). The secondary goal was to determine risk and protective factors for psychiatric comorbidities of these patients. METHODS: From June 2018 to November 2019, patients were recruited from the hospital, Department of Psychiatry. Patients completed baseline surveys after seeing their radiation oncologist and prior to the first treatment, which was scheduled to take place within 7 days (visit 1, baseline); visit 2 occurred within 7 days after RT completion, and visit 3 occurred at 6 weeks after RT completion. A total of 99 patients participated in the study at visit 1; 56 patients completed the study through visit 3. RESULTS: Although changes in psychiatric comorbidities and overall quality of life were observed in patients with breast cancer prior to, during, and after RT, the differences were not significant among visits. Patients diagnosed with psychiatric comorbidities after RT had exhibited risk factors at previous visits, including preexisting psychiatric comorbidities, functional deterioration, and more severe symptoms related to breast cancer. Based on the results, the psychological characteristics of optimism and resilience can be considered as protective factors for psychiatric comorbidities. CONCLUSIONS: The results suggest that early detection and follow-up of psychological distress and poor quality of life at the onset of RT are of paramount importance, and that psychosocial interventions to enhance protective factors (optimism and resilience) may be helpful.

Clinical characteristics and prognostic factors of acquired haemophilia A in Korea.

INTRODUCTION: Acquired haemophilia A (AHA) treatment involves the haemostatic treatment for acute haemorrhage and immunosuppressive therapy (IST) to eradicate FVIII inhibitory antibodies. AIM: We assessed the clinical features of AHA and analysed treatment outcomes in Korea. We further identified prognostic factors affecting treatment outcomes. METHODS: Medical records of 55 patients with AHA from 18 institutions were reviewed retrospectively. Logistic and Cox regression analyses were performed to elucidate clinical factors affecting the achievement of complete remission (CR). The primary endpoint was time to CR after IST, and secondary endpoints were time to haemostasis, the achievement of CR, and overall survival (OS). RESULTS: Among the 55 patients, 50 (91%) had bleeding symptoms. Bleeding was severe in 74% of patients. Thirty-six (72%) patients received haemostatic therapy. Of the 42 patients who received IST, 23 (52%) received steroid alone, with a 52% response rate, and 10 (25%) received a combination of steroid and cyclophosphamide, with an 83% response rate. Five (16%) patients relapsed after a median duration of 220 days. There were eight deaths. In the Cox regression analysis, the FVIII inhibitor titre ≥ 20 BU/mL was the only significant prognostic factor affecting time to CR and haemostasis. No significant difference was observed in OS based on the inhibitor titre. CONCLUSION: The present study demonstrated the demographic data of AHA in Korea and showed that FVIII inhibitory antibody titre was a predictor of time to achieve CR after IST.

Total Platelet Transcriptomics and Its Network Analysis by RNA-Seq and miRNA-Seq and PCA Application in Essential Thrombocythaemia.

Differentiating the aetiology of thrombocytosis is limited yet crucial in patients with essential thrombocythaemia (ET). MicroRNAs (miRNAs) regulate haematopoiesis and lineage commitment; aberrant expression of miRNAs plays an important role in myeloproliferative neoplasms. However, the miRNA profile has been poorly explored in ET patients compared to patients with reactive thrombocytosis (RT). A total of 9 samples, including 5 ET patient samples, 2 RT patient samples, and 2 healthy control samples, were analysed in this study. We produced 81.43 million reads from transcripts and 59.60 million reads from small RNAs. We generated a comprehensive miRNA-mRNA regulatory network and identified unique 14 miRNA expression patterns associated with ET. Among the 14 miRNAs, miR-1268a was downregulated in ET and showed an inverse correlation with its 8 putative target genes, including genes associated with thrombus formation and platelet activation (CDH6, EHD2, FUT1, KIF26A, LINC00346, PTPRN, SERF1A, and SLC6A9). Principal component analysis (PCA) showed ET and non-ET groups well clustered in space, suggesting each group had a distinctive expression pattern of mRNAs and miRNAs. These results suggest that the significant dysregulation of miR-1268a and its 8 target genes could be a unique expression of platelet mi-RNAs and miRNA/mRNA regulatory network in ET patients.

A phase 2 multicenter study of stereotactic body radiotherapy for hepatocellular carcinoma: Safety and efficacy.

BACKGROUND: Although several prospective studies have reported the efficacy of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC), treatment-related toxicity varies and has not been determined. Therefore, the authors evaluated the safety and efficacy of SBRT for patients with HCC in a hepatitis B virus-endemic area. METHODS: This multicenter phase 2 trial enrolled patients with unresectable HCC. Patients received SBRT with 45 to 60 Gy in 3 fractions. To evaluate gastroduodenal toxicity, esophagogastroduodenoscopy (EGD) was performed before and 2 months after SBRT. The primary endpoint was treatment-related severe toxicity at 1 year after SBRT. The secondary endpoints were the 2-year local control, progression-free survival, and overall survival rates. RESULTS: In total, 74 patients were enrolled between January 2012 and April 2015, and 65 eligible patients were analyzed. One patient experienced radiation-induced liver disease with acute grade ≥3 toxicity 1 month after SBRT. In addition, 1 patient had a grade 3 esophageal ulcer with stenosis 5 months after SBRT. The actuarial rate of treatment-related severe toxicity at 1 year was 3%. The pre-SBRT and post-SBRT EGD findings were not significantly different among the 57 evaluable patients who underwent EGD. The 2-year and 3-year local control rates were 97% and 95%, respectively. The progression-free and overall survival rates were 48% and 84% at 2 years, respectively, and 36% and 76% at 3 years, respectively. CONCLUSIONS: With a median follow-up of 41 months, this prospective multicenter study demonstrated that SBRT for patients with HCC is well tolerated and is an effective treatment modality.

Long-term data from a phase 3 study of radotinib versus imatinib in patients with newly diagnosed, chronic myeloid leukaemia in the chronic phase (RERISE).

In the phase 3 study RERISE, patients with newly diagnosed chronic myeloid leukaemia in chronic phase demonstrated significantly faster and higher rates of major molecular response (MMR) with twice-daily radotinib 300 mg (n = 79) or 400 mg (n = 81) than with once-daily imatinib 400 mg (n = 81) after 12 months. With ≥48 months' follow-up, MMR was higher with radotinib 300 mg (86%) or 400 mg (83%) than with imatinib (75%). Among patients with BCR-ABL1 ≤ 10% at three months, MMR and molecular response 4·5 (MR4·5 ) were achieved within 48 months by more radotinib-treated patients (300 mg: 84% and 52%, respectively; 400 mg: 74% and 44%, respectively) than imatinib-treated patients (71% and 44%, respectively). Estimated overall and progression-free survival rates at 48 months were not significantly different between imatinib (94% and 94%, respectively) and radotinib 300 mg (99% and 97%, respectively) or 400 mg (95% and 93%, respectively). The treatment failure rate was significantly higher with imatinib (19%) than with radotinib 300 mg (6%; P = 0·0197) or 400 mg (5%; P = 0·0072). Safety profiles were consistent with previous reports; most adverse events occurred within 12 months. Radotinib continues to demonstrate robust, deep molecular responses, suggesting that treatment-free remission may be attainable.

Nationwide study of paroxysmal nocturnal hemoglobinuria in South Korea: paradox of eculizumab.

Eculizumab is effective in managing patients with paroxysmal nocturnal hemoglobinuria (PNH). In South Korea, the financial support for eculizumab therapy is extended by the National Health Insurance Services (NHIS) only to patients with high-risk PNH for approximately 10 years. In this study, we performed a nationwide analysis of the real-world efficacy of eculizumab therapy in patients diagnosed with PNH between January 1, 2002, and December 31, 2016, by using the NHIS database. Patients treated with eculizumab (the eculizumab-treated group) exhibited a significantly higher survival rate than patients not treated with eculizumab (the eculizumab-untreated group), with 4-year survival rates after propensity score matching of 98.31% and 79.67%, respectively (p = 0.0489). The mean red blood cell (RBC) transfusion units per 12 months after eculizumab therapy were significantly lower than that before eculizumab therapy (5.75 units vs. 12.28 units, p < 0.0001). The median time for the first transfusion in the eculizumab-treated group was significantly longer than that in the eculizumab-untreated group. The 4-year transfusion-independence rate for the eculizumab-treated group was significantly higher than that for the eculizumab-untreated group (20.81% vs. 10.24%, p = 0.078). There was no significant difference between the two groups in the incidence of new documented complications related to PNH. In conclusion, eculizumab therapy for patients with high-risk PNH may effectively improve the survival rate and reduce the transfusion requirement. Paradoxically, eculizumab-treated patients with severe PNH exhibit a higher survival rate than eculizumab-untreated patients with less severe PNH.

Pomalidomide, cyclophosphamide, and dexamethasone for elderly patients with relapsed and refractory multiple myeloma: A study of the Korean Multiple Myeloma Working Party (KMMWP-164 study).

Patients with transplant-ineligible relapsed and refractory multiple myeloma (RRMM) have a short life expectancy, especially when they have failed both the proteasome inhibitor and immunomodulator therapies. This study aimed to assess the efficacy and safety of pomalidomide, cyclophosphamide, and dexamethasone (PCd) in elderly patients with RRMM. This phase 2 clinical trial recruited 55 elderly patients with RRMM. The patients underwent a 28-day treatment cycle: pomalidomide (4 mg/day on days 1-21, administered orally) and cyclophosphamide (400 mg/day on days 1, 8, and 15; administered orally) plus dexamethasone. The median (range) age of the patients was 73.3 (64-86) years, and 8 (14.5%) patients who were ≥ 80 years old. Eight (14.5%) and 31 (56.4%) patients exhibited stage III (revised international staging system) and frail status (simplified frailty scale), respectively. The overall response rate (ORR) and clinical benefit rate (CBR) of PCd therapy were 58.2% and 72.7%, respectively. The median PFS and median overall survival (OS) were 6.90 months (95% CI, 4.7-9.0) and 18.48 months (95% CI, 9.4-27.6), respectively. The incidence rate of grade ≥ 3 non-hematological toxicities was 70.8%. In particular, the incidence rate of primary infection was 45.4%, including 21.8% for pneumonia, 9.0% for sepsis, and 14.6% for febrile neutropenia. In conclusion, PCd is an effective regimen for elderly patients with RRMM who had failed both bortezomib and lenalidomide treatments, but in whom the treatment-associated infection is the main cause of morbidity and mortality.

Treatment with intravenous busulfan, melphalan, and etoposide followed by autologous stem cell transplantation in patients with non-Hodgkin's lymphoma: a multicenter study from the consortium for improving survival of lymphoma.

Several high-dose therapy (HDT) conditioning regimens have been used to treat non-Hodgkin's lymphoma (NHL), such as bis-chloroethylnitrosourea (BCNU)/etoposide/cytosine arabinoside/melphalan (BEAM), BCNU/etoposide/cytosine arabinoside/cyclophosphamide (BEAC), and cyclophosphamide/BCNU/etoposide (CBV). BCNU is an active drug in HDT of NHL, but the supply is limited in some countries, including Korea. Busulfan has been used in allogeneic and autologous stem cell transplantation (ASCT). This phase II study evaluated the efficacy of busulfan/melphalan/etoposide (BuME) as a conditioning regimen for HDT in relapsed or high-risk NHL. The regimen consisted of intravenous busulfan (3.2 mg/kg/day) on days -8, -7, and -6, etoposide (400 mg/m2 /day) on days -5 and -4, and melphalan (50 mg/m2 /day) on days -3 and -2. A total of 46 patients were included in the study, with 36 (78.3%) achieving a complete response after ASCT. The 2-year progression-free survival (PFS) and overall survival (OS) rates for all patients were 46.7% (95% CI, 31.8-60.4%) and 63.7% (95% CI, 47.7-76.0%), respectively. There was no development of veno-occlusive disease and no treatment-related deaths within 100 days after ASCT. These results indicate that a BuME regimen is well-tolerated and effective for patients with relapsed or high-risk NHL, and may be comparable to some previously used regimens. This regimen may be useful as a substitute for BCNU-containing regimens.

Brief report: Clinical experiences after emergency use of daratumumab monotherapy for relapsed or refractory multiple myeloma in real practice.

Despite the recently reported efficacy of daratumumab monotherapy for patients with relapsed or refractory multiple myeloma, outcomes in real practice following daratumumab monotherapy have yet to be investigated. A multi-center retrospective study of 16 Korean patients receiving daratumumab monotherapy for relapsed or refractory multiple myeloma was conducted. The overall response rate was 56.3%. Three patients with creatinine clearance <30 ml/min even achieved an overall response. The median progression-free survival was 2.7 months with 28.9% (95% CI, 9.0-52.8) of 6-month progression-free survival. All infusion-related reactions, including ≥Grade 3 back pain (6.3%) and dyspnea (6.3%), were manageable. The most common hematologic and non-hematological adverse events were anemia (62.5%) and upper respiratory infection (43.8%). ≥Grade 3 bacterial infectious adverse events were identified, including upper and lower respiratory infection (12.5% and 18.8%) and death following sepsis (6.3%). We observed acceptable outcomes of daratumumab monotherapy on relapsed or refractory multiple myeloma patients including even a few subjects with high comorbidity, despite relatively frequent infectious adverse events.

Single-dose etoposide is an effective and safe protocol for stem cell mobilization in patients with multiple myeloma.

BACKGROUND: Single-dose etoposide was used an outpatient-based protocol for mobilization in patients with multiple myeloma (MM) for autologous stem cell transplantation (ASCT). Thus, we retrospectively analyzed the efficacy and safety of our one-day protocol in comparison with that of previous methods. METHODS: We retrospectively analyzed 168 patients with MM who underwent peripheral blood stem cell collection for upfront ASCT between 2008 and 2018. The mobilization protocols included G-CSF alone (G-mobilization), one-day 375 mg/m2 of etoposide (E375), two-days of 375 mg/m2 of etoposide (E750), or one-day high-dose (3.5 g/m2 ) cyclophosphamide (HD CY). For comparison of efficacy of each protocol, collected CD34+ cells over 4 × 106 /kg and under 2 × 106 /kg were defined as "adequate harvest" and "harvest failure," respectively. RESULTS: The median number of collected CD34+ cells was 5.58 × 106 /kg in patients receiving single-dose etoposide, and the percentage of uncomplicated optimal harvest of E375 (65.6%, 21/32) was significantly higher than that of E750 (41.9%, 13/31) and HD CY (31.3%, 15/48). The E375 showed the highest rate of adequate harvest (96.9%, 31/32) compared to that of E750 (87.1%), HD CY (75.0%), and G-mobilization (59.6%). Most E375 patients achieved adequate harvest without complication (29/32, 90.6%), the CD34+ cell collection yield on apheresis days one and two of E375 was not significantly different from that of E750, and no harvest failures occurred for E375. Neutrophil and platelet engraftments were significantly faster in E375 than other groups (P < .001). CONCLUSIONS: The use of single-dose etoposide could be an effective and safe method for mobilization in patients with MM.

The Derived Neutrophil-to-Lymphocyte Ratio Is an Independent Prognostic Factor in Transplantation Ineligible Patients with Multiple Myeloma.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is an independent prognostic marker in solid and hematological cancers. While the derived NLR (dNLR) was shown to be non-inferior to the NLR in large cohorts of patients with different cancer types, it has not been validated as a prognostic marker for multiple myeloma (MM) to date. METHODS: Between May 22, 2011 and May 29, 2014, 176 patients with MM from 38 centers who were ineligible for autologous stem cell transplantation were analyzed. The dNLR was calculated using complete blood count differential data. The optimal dNLR cut-off value according to receiver operating characteristic analysis of overall survival (OS) was 1.51. All patients were treated with melphalan and prednisone combined with bortezomib. RESULTS: The complete response rate was lower in the high dNLR group compared to the low dNLR group (7 vs. 26.1%, respectively; p = 0.0148); the corresponding 2-year OS rates were 72.2 and 84.7%, respectively (p = 0.0354). A high dNLR was an independent poor prognostic factor for OS (hazard ratio 2.217, 95% CI 1.015-4.842; p = 0.0458). CONCLUSION: The dNLR is a readily available and cheaply obtained parameter in clinical studies, and shows considerable potential as a new prognostic marker for transplantation-ineligible patients with MM.

Quality assurance for a multicenter Phase II study of stereotactic ablative radiotherapy for hepatocellular carcinoma ≤5 cm: a planning dummy run.

OBJECTIVE: The Korean Radiation Oncology Group (12-02) investigated the outcome of stereotactic ablative radiotherapy for hepatocellular carcinoma ≤5 cm using 60 Gy in three fractions. To evaluate dosimetric differences and compliance in a multicenter trial, a planning dummy run procedure was performed. METHODS: All six participating institutions were provided the contours of two dummy run cases. Plans were performed following the study protocol to cover the planning target volume with a minimum of 90% of the prescription dose and to satisfy the constraints for organs at risk. We assessed the institutional variations in plans using dose-volume histograms. RESULTS: Different planning techniques were applied: static intensity-modulated radiotherapy in two institutions, CyberKnife in two institutions and RapidArc in two institutions. The conformity index of all 12 plans was ≤1.2. In terms of the planning target volume coverage, all participants followed our study protocol. For the second dummy run case, located in Segment 8 near the heart, the minimum dose of the planning target volume (D99%: dose covering 99% of the planning target volume) was variable because there was no mention of constraints of D99% of the planning target volume in the study protocol. As an important organ at risk, the normal liver volumes receiving <17 Gy in all 12 plans were >700 ml. CONCLUSIONS: Dosimetric parameters showed acceptable compliance with the study protocol. However, we found the possibility of underdose to the planning target volume if the hepatocellular carcinoma lesion was located near organs at risk such as the heart. Based on this dummy run, we will conduct individual case reviews to minimize the effects of study protocol deviation.

A prognostic index for natural killer cell lymphoma after non-anthracycline-based treatment: a multicentre, retrospective analysis.

BACKGROUND: The clinical outcome of extranodal natural killer T-cell lymphoma (ENKTL) has improved substantially as a result of new treatment strategies with non-anthracycline-based chemotherapies and upfront use of concurrent chemoradiotherapy or radiotherapy. A new prognostic model based on the outcomes obtained with these contemporary treatments was warranted. METHODS: We did a retrospective study of patients with newly diagnosed ENKTL without any previous treatment history for the disease who were given non-anthracycline-based chemotherapies with or without upfront concurrent chemoradiotherapy or radiotherapy with curative intent. A prognostic model to predict overall survival and progression-free survival on the basis of pretreatment clinical and laboratory characteristics was developed by filling a multivariable model on the basis of the dataset with complete data for the selected risk factors for an unbiased prediction model. The final model was applied to the patients who had complete data for the selected risk factors. We did a validation analysis of the prognostic model in an independent cohort. FINDINGS: We did multivariate analyses of 527 patients who were included from 38 hospitals in 11 countries in the training cohort. Analyses showed that age greater than 60 years, stage III or IV disease, distant lymph-node involvement, and non-nasal type disease were significantly associated with overall survival and progression-free survival. We used these data as the basis for the prognostic index of natural killer lymphoma (PINK), in which patients are stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high-risk (two or more risk factors) groups, which were associated with 3-year overall survival of 81% (95% CI 75-86), 62% (55-70), and 25% (20-34), respectively. In the 328 patients with data for Epstein-Barr virus DNA, a detectable viral DNA titre was an independent prognostic factor for overall survival. When these data were added to PINK as the basis for another prognostic index (PINK-E)-which had similar low-risk (zero or one risk factor), intermediate-risk (two risk factors), and high-risk (three or more risk factors) categories-significant associations with overall survival were noted (81% [95% CI 75-87%], 55% (44-66), and 28% (18-40%), respectively). These results were validated and confirmed in an independent cohort, although the PINK-E model was only significantly associated with the high-risk group compared with the low-risk group. INTERPRETATION: PINK and PINK-E are new prognostic models that can be used to develop risk-adapted treatment approaches for patients with ENKTL being treated in the contemporary era of non-anthracycline-based therapy. FUNDING: Samsung Biomedical Research Institute.

Efficacy and safety of micafungin versus intravenous itraconazole as empirical antifungal therapy for febrile neutropenic patients with hematological malignancies: a randomized, controlled, prospective, multicenter study.

Micafungin, a clinically important echinocandin antifungal drug, needs to be investigated as empirical therapy in febrile neutropenia in comparison with azole compounds. A prospective randomized study was conducted to compare clinical outcomes between micafungin and intravenous itraconazole as an empirical therapy for febrile neutropenia in hematological malignancies. The antifungal drug (micafungin 100 mg or itraconazole 200 mg IV once daily) was given for high fever that was sustained despite the administration of appropriate antibiotics. Treatment success was determined by composite end points based on breakthrough invasive fungal infection (IFI), survival, premature discontinuation, defervescence, and treatment of baseline fungal infection. Duration of fever, hospital stay, and overall survival (OS) were studied. A total of 153 patients were randomized to receive micafungin or itraconazole. The overall success rate was 7.1 % point higher in the micafungin group (64.4 vs. 57.3 %, p = 0.404), satisfying the statistical criteria for the non-inferiority of micafungin. The duration of fever and hospital stay were significantly shorter in the micafungin group (6 vs. 7 days, p = 0.014; 22 vs. 27 days, p = 0.033, respectively). Grade 3 adverse events including hyperbilirubinemia (2 vs. 7), elevation of transaminase levels (2 vs. 4), electrolyte imbalance (1 vs. 2), atrial fibrillation (1 vs. 0), and anaphylaxis (1 vs. 0) occurred in 7 and 13 patients in the micafungin (10.4 %) and itraconazole (18.8 %) groups, respectively. Micafungin, when compared with itraconazole, had favorably comparable success rate and toxicity profiles on febrile neutropenia in patients with hematological malignancies. In addition, it showed superior effect on shortening the hospital stay.

Comparison of consolidation strategies in acute myeloid leukemia: high-dose cytarabine alone versus intermediate-dose cytarabine combined with anthracyclines.

We compared the efficacy of high-dose cytarabine alone to that of intermediate-dose cytarabine combined with anthracyclines as consolidation therapy. Patients enrolled in the Korea University acute myeloid leukemia (AML) registry received remission induction chemotherapy with the same standard induction regimen (idarubicin and cytarabine 3 + 7). Postremission therapy was performed for three or four cycles according to one of the following regimens: high-dose cytarabine (3 g/m(2)) or combination of intermediate-dose cytarabine (1 g/m(2)) with anthracyclines (idarubicin or mitoxantrone). Among the 443 AML patients enrolled in the registry, 145 patients received consolidation chemotherapy. The median overall survival (OS) and relapse-free survival (RFS) in the high-dose cytarabine group were significantly longer than those in the anthracycline combination group (OS, not reached vs. 16.6 months, p = 0.045; RFS, 38.6 months vs. 11.0 months, p = 0.011). The median duration of neutropenia was longer in the anthracycline combination group than in the high-dose cytarabine group (8 vs. 10 days, p = 0.001). This study suggests that high-dose cytarabine consolidation may produce superior outcomes than combination treatment with intermediate-dose cytarabine and anthracyclines and that the addition of anthracyclines during AML consolidation has limited value as compared to cytarabine intensification.