Impact of Skeletal Muscle Depletion on Patients with Myelodysplastic Syndrome Treated with Azacitidine.

BACKGROUND: Azacitidine (AZA) is the standard treatment for patients with high-risk myelodysplastic syndromes (MDS). The impact of skeletal muscle depletion (SMD), which is associated with outcomes of hematological malignancies, on the clinical course of MDS patients treated with AZA was investigated. METHODS: This retrospective, observational study included 50 MDS patients treated with AZA. Muscle mass was evaluated using the skeletal muscle index (SMI), which is the area of muscle mass at the third lumbar vertebra on CT images divided by the square of the height. RESULTS: Of the enrolled patients, 39 were males, and their median age was 69.5 years. Twenty-seven (20 male and 7 female) patients showed SMD. The median survival was 13.4 months in the SMD group and 15.2 months in the non-SMD group, with no significant difference and no significant association between the response rate or severe non-hematological toxicities and the presence of SMD. By contrast, grade 3-4 anemia and thrombocytopenia were significantly more frequent in the SMD group than in the non-SMD group. SMD was associated with severe anemia and thrombocytopenia in MDS patients treated with AZA. CONCLUSION: Reduced skeletal muscle mass may predict severe hematological toxicity in MDS patients treated with AZA.

Cohort profile: rationale and design of the Resource Center for Health Science (RECHS) project - a study of health hazards and medical cost burden among the Japanese population.

PURPOSE: The increased global burden of non-communicable diseases and mental disorders is an urgent health challenge for countries around the entire world, especially those experiencing super-ageing societies, where over 21% of the population is age 65 years or older. Japan is the world's most rapidly ageing society, and as a result, medical costs are also rising dramatically. With the aims of establishing a foundational framework for future research efforts, primarily focusing on the development of a personal health record (PHR) system, and creating a long-term repository for bioresources integrated with PHRs, this study investigated potential health risks and future healthcare burdens based on a longitudinal analysis of health records. PARTICIPANTS: The Resource Center for Health Science (RECHS) project is a long-term, prospective biobank project, population and health check-up-based cohort that primarily investigates the associations between lifestyle and environmental factors and some surrogate markers of non-communicable diseases, such as diabetes, hypertension, cardiovascular disease and cancer. Starting in 2010, we initiated an annual cohort study among voluntary participants recruited from health check-up programmes and collected data from the following sources: a self-administered baseline questionnaire that included items on dietary habits and stress, a Brief Self-Administered Diet History Questionnaire, the Centre for Epidemiologic Studies Depression Scale and the General Health Questionnaire-28. FINDINGS TO DATE: For this prospective cohort study, we planned to enrol approximately 10 000 participants. We collected and stored serum samples from all participants for future analyses. The study participants who still were able to participate in these health check-ups and their outcomes were then obtained from the measurements and questionnaire responses. FUTURE PLANS: Insights emerging from the RECHS study can provide researchers and public health policy administrators with evidence to aid in the prevention of non-communicable diseases and clarify the most malleable status to implement preventive measures.

The pretreatment Controlling Nutritional Status score is an independent prognostic factor in elderly patients with diffuse large B-cell lymphoma.

Predicting prognosis is crucial in older patients with diffuse large B-cell lymphoma (DLBCL). This study evaluated the prognostic impact of the controlling nutritional status (CONUT) score, a simple nutritional index, for older DLBCL patients (≥65 years of age) treated with R-CHOP-like regimens in a retrospective, cohort study including 203 patients. The CONUT score was an independent prognostic factor for overall survival (hazard ratio 1.11, 95% confidence interval (CI) 1.01-1.21, p = 0.032) in a multivariable Cox proportional hazards model. On receiver-operating characteristic analysis, the optimal cutoff value was 3. The CONUT score (≥3 or <3) effectively stratified older DLBCL patients, regardless of the International Prognostic Index (p = 0.71 for interaction). Further, the CONUT score independently affected initial dose intensity (odds ratio 0.84, 95% CI 0.73-0.95, p = 0.008), likely reflecting the patients' status at diagnosis and affecting dose adjustments. In conclusion, the CONUT score is associated with a poorer prognosis in older DLBCL patients.

Comparison of the prognostic impact of IPI and PIT in peripheral T-cell lymphoma in real-world practice with a large elderly population.

We compared the predictive ability of the International Prognostic Index (IPI), a frequently used prognostic model for peripheral T-cell lymphoma (PTCL), with that of a type-specific prognostic model, the Prognostic Index for PTCL-U (PIT). We retrospectively analyzed 113 patients diagnosed with PTCL. The median age was 67 years (range, 16-88 years), 75 patients (66%) were male, and the most common disease type was PTCL, not otherwise specified (69%). With a median follow-up of 6.8 years (interquartile range, 2.7-9.9 years), 5-year survival rates for the four groups in IPI were 85%, 62%, 49%, and 13%, respectively. Similarly, 5-year survival rates for the four groups in PIT were 83%, 64%, 49%, and 19%, respectively. The area under the receiving operating characteristic curve for predicting mortality from PIT (0.725) was not significantly different from that from the IPI (0.685, P = 0.134). Multivariable analysis showed that performance status ≥ 2 (P < 0.0001) and extranodal lesions ≥ 2 (P = 0.029) were significantly associated with lower overall survival. The present study found no significant difference in prognostic ability between the IPI and PIT for PTCL, and both models appear useful as predictive models.

The Relative Dose Intensity Changes during Cycles of Standard Regimens in Patients with Diffuse Large B-Cell Lymphoma.

No studies have focused on the trajectory of the average relative dose intensity (ARDI) during cycles of first-line chemotherapy for patients with diffuse large B-cell lymphoma. To evaluate the impact of attenuating ARDI during cycles on overall survival, we conducted a multi-centre, longitudinal, observational retrospective study. A total of 307 analysable patients were enrolled. Multivariate Cox hazards modelling with restricted cubic spline models revealed prognostic benefits of higher ARDI up to, but not after, cycle 6. According to group-based trajectory modelling, patients were classified into five groups depending on the pattern of ARDI changes. Among these, two groups in which ARDI had fallen significantly to less than 50% by cycles 4-6 displayed significantly poorer prognosis, despite increased ARDI in the second half of the treatment period (log-rank p = 0.02). The Geriatric Nutritional Risk Index offered significant prediction of unfavourable ARDI changes (odds ratio 2.540, 95% confidence interval 1.020-6.310; p = 0.044). Up to cycle 6, maintenance of ARDI in all cycles (but particularly in the early cycles) is important for prognosis. Malnutrition is a significant factor that lets patients trace patterns of ARDI changes during cycles of chemotherapy associated with untoward prognosis.

Effects of door-to-tolvaptan time on short-term clinical outcome in patients with acute heart failure.

AIMS: We investigated the effects of door-to-tolvaptan (D2T) time on short-term urine volume and in-hospital clinical outcomes in patients with acute heart failure (AHF). METHODS AND RESULTS: Patients with AHF, treated with tolvaptan at two hospitals, were enrolled in this retrospective observational study. The D2T time was defined as the time elapsed from the arrival of a patient at a participating hospital to the first administration of tolvaptan. The group with the D2T time within 6 h was defined as the 'early group'. The primary outcome was 48-h urine volume. The secondary outcomes were in-hospital death, length of hospital stay, and worsening renal function (WRF) incidence. A restricted cubic spline model was used to evaluate the presence of a nonlinear association between the D2T time and 48-h urine volume and the odds ratio of WRF incidence. Our study included a total of 138 patients with AHF who were started on tolvaptan after hospitalization. The median D2T time was 5.3 h (interquartile range: 3.0-31.9 h). Seventy-four patients (53.6%) were classified to be in the early group. Baseline characteristics were similar in the two groups: mean age (85.4 ± 9.6 years vs. 84.5 ± 9.5 years; P = 0.59) and male sex (n = 22 [33.3%] vs. n = 29 [46%]; P = 0.16), except that patients in the early group had higher systolic blood pressure than those in the delayed group (138.2 ± 22.9 vs. 125.7 ± 21.7; P = 0.001). The initial tolvaptan dose in the delayed group was much lower than that in the early group (7.5 [7.5, 7.5] vs. 7.5 [5.6, 7.5] mg; P = 0.01). Total urine volume in 48 h did not differ in the early and delayed groups (4113 ± 1758 mL vs. 4201 ± 1893 mL; P = 0.80). The relationship between D2T time and total urine volume within 48 h increased slightly, with a peak at a D2T time of 15 h, and gradually decreased, thereafter. In-hospital death and the length of hospital stay did not differ significantly between the two groups (n = 1, 1.3% vs. n = 4, 6.3%; P = 0.18, and 5.0 [12.0, 30.0] vs. 22.0 [14.5, 30.0] days; P = 0.17, respectively). Notably, the restricted cubic spline model for the odds ratio of WRF incidence increased as the D2T time was delayed (P for effect<0.01). CONCLUSIONS: The shorter D2T time did not affect the short-term urine volume and in-hospital outcomes but reduced the risk of WRF incidence in patients with AHF.

Prognostic significance of the Geriatric 8 score alone and included with genetic risk group in older adults with acute myeloid leukemia.

INTRODUCTION: As the numbers of older adult patients with acute myeloid leukemia (AML) continue to increase, the establishment of a simple geriatric assessment specifically for AML represents an unmet need. This study aimed to assess the impact of the Geriatric 8 (G8) score on overall survival (OS). MATERIALS AND METHODS: We retrospectively analyzed 100 patients ≥60 years old with newly diagnosed AML. RESULTS: Multivariate Cox modeling identified G8 score as a significant prognostic factor for OS (hazard ratio 0.891, 95% confidence interval [CI] 0.808-0.983). A linear association between G8 score and mortality risk was confirmed in a Cox model with restricted cubic spline. Multivariate receiver operating characteristic curves demonstrated a significant improvement in prediction ability when G8 score was added to cytogenetic risk group. The combination of G8 score and cytogenetic risk group yielded a significant continuous net reclassification improvement (0.718; 95%CI 0.353-1.082; P < 0.001). Decision curve analysis showed a clinical net benefit associated with adding G8 score to cytogenetic risk group. DISCUSSION: G8 score not only offered a strong prognostic factor for OS, but also markedly improved prediction accuracy for mortality when incorporated with cytogenetic risk group.

The Japanese Guide affected the prescription of steroids for COVID-19 inpatients during the COVID-19 epidemic in Japan.

Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, guidance ("Japanese Guide") has been published by a working group of several academic societies and announced by the Ministry of Health, Labour, and Welfare. Steroids as a candidate treatment for COVID-19 were noted in the Japanese Guide. However, the prescription details for steroids, and whether the Japanese Guide changed its clinical practice, were unclear. This study aimed to examine the impact of the Japanese Guide on the trends in the prescription of steroids for COVID-19 inpatients in Japan. We selected our study population using Diagnostic Procedure Combination (DPC) data from hospitals participating in the Quality Indicator/Improvement Project (QIP). The inclusion criteria were patients discharged from hospital between January 2020 and December 2020, who had been diagnosed with COVID-19, and were aged 18 years or older. The epidemiological characteristics of cases and the proportion of steroid prescriptions were described on a weekly basis. The same analysis was performed for subgroups classified by disease severity. The study population comprised 8603 cases (410 severe cases, 2231 moderate II cases, and 5962 moderate I/mild cases). The maximum proportion of cases prescribed with dexamethasone increased remarkably from 2.5 to 35.2% in the study population before and after week 29 (July 2020), when dexamethasone was included in the guidance. These increases were 7.7% to 58.7% in severe cases, 5.0% to 57.2% in moderate II cases, and 1.1% to 19.2% in moderate I/mild cases. Although the proportion of cases prescribed prednisolone and methylprednisolone decreased in moderate II and moderate I/mild cases, it remained high in severe cases. We showed the trends of steroid prescriptions in COVID-19 inpatients. The results showed that guidance can influence drug treatment provided during an emerging infectious disease pandemic.

Prognostic value of metabolic tumor volume of extranodal involvement in diffuse large B cell lymphoma.

Extranodal involvement predicts poor outcomes of diffuse large B cell lymphoma (DLBCL), but the impact of the metabolic tumor burden (MTV) of extranodal sites using positron emission tomography has not been clarified. This study aimed to assess the impact of extranodal MTV on overall survival (OS). We retrospectively analyzed 145 newly diagnosed DLBCL patients and verified the prognostic impact of each extranodal and nodal MTV. Multivariate Cox hazards modelling using both extranodal and nodal MTV as covariables identified extranodal MTV as a significant factor for OS (hazard ratio [HR] 1.072, 95% confidence interval [CI] 1.019-1.129, P = 0.008), but not nodal MTV. Multivariate Cox modelling using restricted cubic splines demonstrated that the impact of total MTV depends on the MTV of extranodal sites, not of nodal sites. When both the number and MTV of extranodal involvements were used as covariables, extranodal MTV remained a significant predictor of OS (HR 1.070, 95%CI 1.017-1.127, P = 0.009), but the number of extranodal sites did not. Extranodal MTV potentially had a more significant role on prognosis than nodal MTV. When considering prognostic impacts, the MTV of extranodal involvement is significantly more important than the number.

Impact of policy alterations on elective percutaneous coronary interventions in Japan.

OBJECTIVE: Establishing appropriate percutaneous coronary intervention (PCI) in stable angina pectoris (SAP) has become a distinctive performance measure worldwide. Clinical guidelines call for documenting ischaemia in patients with SAP prior to elective PCI. The Japanese Ministry of Health, Labour and Welfare introduced a new reimbursement policy in April 2018 to promote the appropriate and judicious implementation of PCI. The 2018 reimbursement changes clarified the required proof of ischaemia. Tests to evaluate functional ischaemia and coronary stenosis have been added as a requirement for reimbursement. We examined whether this reimbursement revision had an impact on PCI procedures for SAP in Japan. METHODS: We used administrative claims data in Japan's Diagnosis Procedure Combination database from April 2014 through March 2020. We used interrupted time series analyses with a control to ascertain the impacts on elective PCI procedures before and after the Japanese reimbursement revision. The primary outcome was the change in elective PCI procedures per month. Emergent PCI procedures served as a control group. RESULTS: A total of 773 240 PCI procedures were identified between April 2014 and March 2020: 388 817 and 180 462 elective PCIs before and after the reimbursement revision, respectively. After the 2018 reimbursement revision, significant trend changes were found in elective PCI procedures per month (-106.3, 95% CI -155.8 to -56.8, p<0.01), while the number of emergent PCIs remained stable throughout the study period. CONCLUSIONS: After revising the reimbursement tariff for elective PCIs in 2018, there was a significant reduction in elective PCI procedures per month.

Prognostic value of 1,5-anhydro-D-glucitol incorporating syntax score in acute coronary syndrome.

The utility of adding information on 1,5-anhydro-D-glucitol (1,5-AG), a marker for postprandial hyperglycemia, to a pre-existing scoring system in acute coronary syndrome (ACS) patients is unknown. This retrospective cohort study included 266 ACS patients. The end point was major adverse cardiac and cerebral events (MACCE) through 5 years of follow-up. To evaluate incremental benefits of combining 1,5-AG with the syntax score, we applied time-dependent receiver operating curve (ROC) analysis, net reclassification improvement (NRI), integrated discrimination improvement (IDI) and decision curve analysis (DCA). Temporal changes to the area under time-dependent ROC curves showed that addition of 1,5-AG parameters to syntax score did not provide any incremental value (area under the curve for syntax alone, 0.673 (95% confidence interval (CI), 0.599-0.747) vs. with 1,5-AG combined, 0.671 (95%CI 0.596-0.746; Delong p = 0.65). Incorporating 1,5-AG into syntax score yielded a significant NRI of 0.291 (95%CI 0.015-0.567) and IDI of 0.055 (95%CI 0.018-0.093), while DCA analysis showed the limited net benefit in combination with 1,5-AG and syntax score. 1,5-AG values exhibited significant discriminatory utility for detecting MACCE within the ACS population. However, 1,5-AG levels contributed limited utility beyond syntax score based on time-dependent ROC and DCA analyses.Trial registration: UMIN000023837.

The Trajectory of the COVID-19 Vaccine Antibody Titers Over Time and the Association of Mycophenolate Mofetil in Solid Organ Transplant Recipients.

The COVID-19 vaccine will be safe and effective in solid organ transplant recipients (SOTs). However, the blunted antibody responses were also of concern. Few studies have reported prolonged serologic follow-up after 2 doses of BNT162b2 vaccine in SOTs. We performed a single-center, prospective observational study of 78 SOTs who received 2 doses of BNT162b2 vaccine. We identified the trajectory of antibody titers after vaccination among SOTs with or without mycophenolate mofetil (MMF) or withdrawn from MMF. We found low seroconversion rates (29/42: 69%) and low antibody titers in SOTs treated with MMF. An inverse linear relationship between neutralizing antibody titers and MMF concentration was confirmed in restricted cubic spline plots (P for effect < .01, P for nonlinearity = .08). For the trajectory of antibody responses, seroconversion and improved antibody titers were observed after withdrawal from MMF in SOTs who showed seronegative or low antibody titers at the first visit after 2 doses of vaccine (P for effect < .01, P for nonlinearity < .05, and P for interaction < .01). We identified increased B-cell counts after withdrawal from MMF (P < .01). The recovery of antibody responses was seen in SOTs withdrawn from MMF. The trajectories of antibody responses were modified by MMF administration.

Medium-term impacts of the waves of the COVID-19 epidemic on treatments for non-COVID-19 patients in intensive care units: A retrospective cohort study in Japan.

BACKGROUND: Maintaining critical care for non-Coronavirus-disease-2019 (non-COVID-19) patients is a key pillar of tackling the impact of the COVID-19 pandemic. This study aimed to reveal the medium-term impacts of the COVID-19 epidemic on case volumes and quality of intensive care for critically ill non-COVID-19 patients. METHODS: Administrative data were used to investigate the trends in case volumes of admissions to intensive care units (ICUs) compared with the previous years. Standardized mortality ratios (SMRs) of non-COVID-19 ICU patients were calculated in each wave of the COVID-19 epidemic in Japan. RESULTS: The ratios of new ICU admissions of non-COVID-19 patients to those in the corresponding months before the epidemic: 21% in May 2020, 8% in August 2020, 9% in February 2021, and 14% in May 2021, approximately concurrent with the peaks in COVID-19 infections. The decrease was greatest for new ICU admissions of non-COVID patients receiving invasive mechanical ventilation (IMV) on the first day of ICU admission: 26%, 15%, 19%, and 19% in the first, second, third, and fourth waves, respectively. No statistically significant change in SMR was observed in any wave of the epidemic; SMRs were 0.990 (95% uncertainty interval (UI), 0.962-1.019), 0.979 (95% UI, 0.953-1.006), 0.996 (95% UI, 0.980-1.013), and 0.989 (95% UI, 0.964-1.014), in the first, second, third, and fourth waves of the epidemic, respectively. CONCLUSIONS: Compared to the previous years, the number of non-COVID-19 ICU patients continuously decreased over the medium term during the COVID-19 epidemic. The decrease in case volumes was larger in non-COVID-19 ICU patients initially receiving IMV than those undergoing other initial treatments. The standardized in-hospital mortality of non-COVID-19 ICU patients did not change in any waves of the epidemic.

Successful removal of a broncholith using a cryo-probe under rigid bronchoscopy: A case report.

Broncholithiasis is a rare condition in which lymph nodes, cartilage or inhaled material in the bronchi become calcified. Removal of the broncholith is indicated when it causes symptoms such as hemoptysis and obstructive pneumonia. Although there are various methods for removing broncholiths, no international recommendations exist. We report a case of safe removal of broncholiths using a cryo-probe under rigid bronchoscopy. A 72-year-old man presented with blood-tinged sputum for 5 months. Chest computed tomography (CT) revealed collapse of the middle lung lobe. Flexible bronchoscopy demonstrated broncholiths at the orifice of the middle lobe. We successfully removed the broncholiths with a cryo-probe under rigid bronchoscopy without any complications. Our experience suggests that removal of broncholiths can be safely and successfully performed using a cryo-probe under rigid bronchoscopy.

Prediction of Technical Failure of Inframalleolar Angioplasty in Patients with Chronic Limb Threatening Ischaemia.

OBJECTIVE: This study sought to: determine anatomically evaluated predictors of the technical failure of inframalleolar angioplasty (IMA), develop a predictive model for unsuccessful IMA, and investigate the effect of IMA on clinical outcomes in patients with chronic limb threatening ischaemia (CLTI). METHODS: This single centre retrospective observational study enrolled 159 patients with CLTI who underwent IMA for de novo occluded lesions between November 2017 and May 2021. These patients were divided into two groups: the Failed IMA group (n = 62) and the Successful IMA group (n = 97). RESULTS: In multivariable analysis, no target vessel outflow (OR 39.8, 95% CI 10.7 - 148, p < .001), medial artery calcification (MAC) grade (OR 4.91, 95% CI 1.40 - 17.3, p = .010), and occluded pedal arch (OR 5.2, 95% CI 1.2 - 22.7, p = .030) were identified as independent predictors of IMA technical failure. The risk prediction model had an area under the receiver operating characteristic curve (AUC) of 0.93; after bootstrapping adjustment for optimism, this value represented a corrected AUC of 0.95. The patients in the Successful IMA group had a significantly higher proportion of wound healing at 12 months than those in the Failed IMA group (log rank p = .030). IMA technical failure was associated with a significant change in the proportion of wound healing (HR 0.59, 95% CI 0.37- 0.94, p = .030). CONCLUSION: No target vessel outflow, MAC grade, and occluded pedal arch were independent predictors of IMA technical failure. Additionally, successful IMA was associated with better wound healing outcomes at 12 months. Furthermore, a model incorporating these three predictors precisely predicted IMA technical failure.

Relationship of body mass index to clinical outcomes after percutaneous coronary intervention.

BACKGROUND: Elevated body mass index (BMI) demonstrates lower all-cause and cardiovascular mortalities compared with normal-weight or lean patients in chronic diseases. This study investigated relationships between BMI and clinical outcomes following percutaneous coronary intervention (PCI) in coronary artery disease (CAD) patients, together with the sex-specific impacts of BMI on mortality. METHODS: We reviewed 1104 CAD patients who underwent PCI between 2006 and 2015. Patients were divided by BMI into three groups: lean, <18.5 kg/m2 ; normal, 18.5-24.9 kg/m2 ; and overweight/obese, ≥25 kg/m2 . The primary endpoint was all-cause mortality, and the secondary endpoint was 3-point major adverse cardiovascular events (MACE). RESULTS: Kaplan-Meier survival analysis demonstrated risks of all-cause death, and 3-point MACE were higher in lean patients compared with normal-weight and overweight/obese subjects (log-rank p < .001). Cox proportional hazard modelling showed overweight/obese was significantly associated with all-cause death (hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.48-0.95; p = .03), and lean was significantly associated with 3-point MACE (HR 2.02, 95% CI 1.15-3.53; p = .01). Cox proportional hazard analysis with restricted cubic spline showed non-linear associations between BMI and both all-cause mortality and 3-point MACE (p for effect = .002 and = .003, respectively). No significant interaction was evident between sex and BMI for all-cause mortality (p for interaction = .104) or 3-point MACE (p for interaction =0.122). CONCLUSIONS: Lean category was associated with adverse outcomes among CAD patients. An obesity paradox regarding the independent association of elevated BMI with reduced mortality after PCI is evident in both males and females.

Hemophagocytic syndrome due to Epstein-Barr virus and cytomegalovirus coinfection in a patient on adalimumab.

INTRODUCTION: Hemophagocytic syndrome (HPS) is a rare but potentially fatal complication of viral infections. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) often infect patients receiving TNF-alpha inhibitors (TNF-α inhibitors). While EBV and CMV are well established infections for the development of infectious mononucleosis, coinfection with EBV and CMV is common among immunosuppressed patients and can result in a fatal course. In addition, such viral infections can cause HPS. To the best of our knowledge, we present here the first report of HPS induced by EBV and CMV coinfection during anti-TNFα inhibitor use. CASE REPORT: A 23-year-old man hospitalized with fever, elevated liver enzymes, lymphadenopathy, and hepatosplenomegaly was diagnosed with HPS associated with EBV and CMV coinfection while using adalimumab. No clinical improvement was observed after discontinuation of adalimumab. HPS complicated by EBV and CMV coinfection was finally diagnosed, and immediate administration of ganciclovir and prednisone was considered to have prevented a lethal clinical outcome. CONCLUSION: For cases showing unexplained fever, elevated liver enzymes, and lymphadenopathy while using anti-TNFα inhibitors, screening for EBV and CMV coinfection should be encouraged. In addition, HPS should be considered in patients with EBV and/or CMV infection receiving anti-TNFα inhibitors to facilitate early definitive therapy.