Changes in chronic myeloid leukemia treatment modalities and outcomes after introduction of second-generation tyrosine kinase inhibitors as first-line therapy: a multi-institutional retrospective study by the CML Cooperative Study Group.

This study investigated changes in treatment modalities and outcomes of chronic myeloid leukemia in the chronic phase (CP-CML) after the approval of second-generation tyrosine kinase inhibitors (2G-TKIs) for first-line therapy. Patients were grouped into those who underwent TKI therapy up to December 2010 (imatinib era group, n = 185) and after January 2011 (2G-TKI era group, n = 425). All patients in the imatinib era group were initially treated with imatinib, whereas patients in the 2G-TKI era group were mostly treated with dasatinib (55%) or nilotinib (36%). However, outcomes including progression-free survival, overall survival, and CML-related death (CRD) did not differ significantly between groups. When stratified by risk scores, the prognostic performance of the ELTS score was superior to that of the Sokal score. Even though both scoring systems predicted CRD in the imatinib era, only the ELTS score predicted CRD in the 2G-TKI era. Notably, the outcome of patients classified as high-risk by ELTS score was more favorable in the 2G-TKI era group than in the imatinib era group. Thus, expanding treatment options may have improved patient outcomes in CP-CML, particularly in patients classified as high-risk by ELTS score.

Synthesis of the A/D/E-ring Core Compounds of Maoecrystal V†.

Synthesis of the A/D/E-ring core compounds of maoecrystal V was achieved. The key Diels-Alder reactions between tricyclic α-methylene lactones and Kitahara-Danishefsky dienes afforded the spirocyclic core compounds in a regioselective and stereoselective manner.

Outcomes of 30 Gy/5 Fr Hypofractionated Stereotactic Radiation Therapy for Small Brain Metastases (≤2 cm).

BACKGROUND/AIM: Stereotactic radiosurgery (SRS)-used for brain metastases (BMs) with a tumor diameter of ≤2 cm-has a high local control rate, however, it can cause symptomatic radiation-induced brain necrosis. Hypofractionated stereotactic radiation therapy (HFSRT) is not commonly used for such lesions and its effectiveness remains unknown. Herein, the efficacy of 30 Gy 5-fraction HFSRT for treating BMs of <2 cm was retrospectively evaluated. PATIENTS AND METHODS: Patients who received HFSRT and had a gross tumor volume (GTV) of ≤2 cm in maximum diameter were included in the study (49 patients; 179 BMs; median follow-up period, 11.9 months). RESULTS: The mean GTV Peripheral Dose (D95) was 36.2 Gy. The local control (LC) rates at 1 and 2 years were 93.0% and 81.5%, respectively, for all lesions. The 1-year LC rates were 93.6% and 92.0% for ≤1.0-cm and 1.0-2.0-cm lesions, respectively. Multivariate analysis revealed that the only significant difference was in GTV maximal tumor diameter (HR=1.961, p=0.0002). Notably, only one patient had asymptomatic radiation necrosis. CONCLUSION: Owing to the high toxicity of SRS, 5-fraction HFSRT can be an effective treatment strategy for BMs of <2 cm.

Clinical management of second-generation tyrosine kinase inhibitor therapy in patients with newly diagnosed chronic myeloid leukemia in the chronic phase, focusing on age and dose effects.

ABL1-tyrosine kinase inhibitors (TKIs) are an established treatment choice for patients with chronic myeloid leukemia in the chronic phase (CML-CP). However, effects of TKI dose modification have not been well investigated. In this study, we retrospectively analyzed 178 patients with newly diagnosed CML-CP who were treated with dasatinib or nilotinib, focusing on age and dose effects. Efficacy as measured by cumulative major molecular response (MMR) and molecular response 4.5 rates did not differ significantly between the younger group and elderly group. Elderly patients who started nilotinib at a reduced dose had similar or better efficacy outcomes (including cumulative MMR and continuation ratios) than other groups, and elderly patients who started dasatinib at a reduced dose had the lowest MMR ratio and longest MMR duration. Effects of dose modification based on age and TKI selection can be attributed to flexible management of TKI therapy in real-world practice, but further studies are required to validate the findings of this study.

Management and Risk Factors for Pleural Effusion in Japanese Patients with Chronic Myeloid Leukemia Treated with First-line Dasatinib in Real-world Clinical Practice.

Objective Pleural effusion (PE) is a common adverse event that occurs during dasatinib therapy for chronic myeloid leukemia (CML). However, the pathomechanism of PE and appropriate management of Asian patients with CML have not been elucidated. This study investigated the incidence rate, risk, and appropriate management of PE in Asian patients with CML treated with dasatinib. Methods We retrospectively collected data on patients in the chronic phase of CML who received first-line dasatinib therapy and were registered in the CML-Cooperative Study Group database. Patients We identified 44 cases of PE in a series of 89 patients and analyzed previously reported risk factors and effective management of PE. Results A univariate analysis revealed that age, diabetes mellitus, chronic renal failure, hypertension, the history of cardiovascular events, and dasatinib dose were significantly associated with PE. A multivariate analysis revealed that age ≥65 years old was the only independent risk factor for PE. Dasatinib dose reduction and switching to a tyrosine kinase inhibitor showed a statistically significant difference in effectively reducing PE volume compared to single diuretic use. Conclusion Although further studies are warranted, our observations showed that advanced age is a significant risk factor for PE, and tyrosine kinase inhibitor dose reduction or replacement of dasatinib may be an effective management strategy for PE in Asian CML patients who received first-line treatment with dasatinib in real-world clinical practice.

Cricotracheostomy for patients with severe COVID-19: A case control study.

Background: Tracheostomy is an important procedure for the treatment of severe coronavirus disease-2019 (COVID-19). Older age and obesity have been reported to be associated with the risk of severe COVID-19 and prolonged intubation, and anticoagulants are often administered in patients with severe COVID-19; these factors are also related to a higher risk of tracheostomy. Cricotracheostomy, a modified procedure for opening the airway through intentional partial cricoid cartilage resection, was recently reported to be useful in cases with low-lying larynx, obesity, stiff neck, and bleeding tendency. Here, we investigated the usefulness and safety of cricotracheostomy for severe COVID-19 patients. Materials and methods: Fifteen patients with severe COVID-19 who underwent cricotracheostomy between January 2021 and April 2022 with a follow-up period of ≥ 14 days were included in this study. Forty patients with respiratory failure not related to COVID-19 who underwent traditional tracheostomy between January 2015 and April 2022 comprised the control group. Data were collected from medical records and comprised age, sex, body mass index, interval from intubation to tracheostomy, use of anticoagulants, complications of tracheostomy, and decannulation. Results: Age, sex, and days from intubation to tracheostomy were not significantly different between the COVID-19/cricotracheostomy and control/traditional tracheostomy groups. Body mass index was significantly higher in the COVID-19 group than that in the control group (P = 0.02). The rate of use of anticoagulants was significantly higher in the COVID-19 group compared with the control group (P < 0.01). Peri-operative bleeding, subcutaneous emphysema, and stomal infection rates were not different between the groups, while stomal granulation was significantly less in the COVID-19 group (P = 0.04). Conclusions: These results suggest that cricotracheostomy is a safe procedure in patients with severe COVID-19.

Mutational analysis of DNMT3A improves the prognostic stratification of patients with acute myeloid leukemia.

Nucleophosmin1 (NPM1) mutations are the most frequently detected gene mutations in acute myeloid leukemia (AML) and are considered a favorable prognostic factor. We retrospectively analyzed the prognosis of 605 Japanese patients with de novo AML, including 174 patients with NPM1-mutated AML. Although patients with NPM1-mutated AML showed a high remission rate, this was not a favorable prognostic factor for overall survival (OS); this is contrary to generally accepted guidelines. Comprehensive gene mutation analysis showed that mutations in codon R882 of DNA methyltransferase 3A (DNMT3AR882 mutations) were a strong predicative factor indicating poor prognosis in all AML (p < 0.0001) and NPM1-mutated AML cases (p = 0.0020). Furthermore, multivariate analysis of all AML cases showed that DNMT3AR882 mutations and the co-occurrence of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD), NPM1 mutations, and DNMT3AR882 mutations (triple mutations) were independent factors predicting a poor prognosis related to OS, with NPM1 mutations being an independent factor for a favorable prognosis (hazard ratios: DNMT3AR882 mutations, 1.946; triple mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3AR882 mutations and triple mutations on prognosis and according to the classification of NPM1-mutated AML into three risk groups based on DNMT3AR882 /FLT3-ITD genotypes, we achieved the improved stratification of prognosis (p < 0.0001). We showed that DNMT3AR882 mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3AR882 mutations were excluded, NPM1 mutations were a favorable prognostic factor. This revealed that ethnological prognostic discrepancies in NPM1 mutations might be corrected through prognostic stratification based on the DNMT3A status.

Laryngeal complications after endotracheal intubation and prone positioning in patients with coronavirus disease 2019.

Objectives: Laryngeal complications have been reported after endotracheal intubation and prone positioning in patients with critical coronavirus disease 2019 (COVID-19), but their association is unclear. In this study, we investigated the rate of laryngeal complications in patients with COVID-19 compared to an alternative condition (control group). Methods: We retrospectively analyzed the data of 40 patients who underwent endotracheal intubation for either COVID-19 or an alternative condition (control group). Data on age, sex, body mass index (BMI), cardiovascular disease (CVD) risk factors, use of prone therapy, duration of endotracheal intubation, and duration from extubation/tracheostomy to laryngeal evaluation were collected from medical records. Results: There were no significant differences in BMI, frequency of CVD risk factors, duration of endotracheal intubation, or duration from extubation/tracheostomy to laryngeal evaluation between the two groups. In the COVID-19 group, all patients adopted the prone position. In comparison, only one patient in the control group adopted the prone position. Significant differences were observed between the two groups regarding the incidence of vocal fold immobility and laryngeal granuloma. Conclusion: Laryngeal complications were more common in the COVID-19 group than in the control group. Prone positioning may be a risk factor for these complications. Level of Evidence: 4.

Outcomes of adolescents and young adults with chronic-phase chronic myeloid leukaemia treated with tyrosine kinase inhibitors.

INTRODUCTION: Few studies have reported the outcomes of adolescents and young adults (AYAs) with chronic-phase chronic myeloid leukaemia (CML-CP) on tyrosine kinase inhibitors (TKIs). MATERIALS AND METHODS: We retrospectively analysed the clinical features, treatment response, and long-term outcomes of 42 AYA patients, in comparison to older patients. The initial therapies of AYA patients between 2001 and 2016 included imatinib (n = 24), dasatinib (n = 13) and nilotinib (n = 5). RESULTS: In AYA patients, the peripheral blood (PB) white blood cell count and percentage of blasts at the diagnosis were significantly higher, haemoglobin levels were lower and the spleen size was larger. The major molecular response (MMR), event-free survival (EFS) and overall survival (OS) rates were comparable. A sub-analysis comparing imatinib to second-generation TKIs as the initial therapy also showed that their prognosis was comparable. DISCUSSION: In conclusion, the tumour burden at the diagnosis of CML-CP is higher in AYA patients; however, their prognosis was not worse in comparison to older patients treated with TKIs. KEY MESSAGESFew studies have reported the outcomes of adolescents and young adults (AYAs) with chronic-phase chronic myeloid leukaemia (CML-CP) on tyrosine kinase inhibitors (TKIs). This study showed the tumour burden at the diagnosis of CML-CP is higher in AYA pa tients; however, their prognosis was not worse in comparison to older patients treated with TKIs. Understanding the biological and non-biological features of AYA patients with CML-CP on TKI therapy is essential for better management and to improve the outcomes.

NPM1-mutation-based measurable residual disease assessment after completion of two courses of post-remission therapy is a valuable clinical predictor of the prognosis of acute myeloid leukemia.

Recent studies have reported that measurable residual disease (MRD) analysis using NPM1 mutations helps determine whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated in acute myeloid leukemia (AML) patients. However, the optimal timing and cutoff value for measuring MRD using genomic DNA remain undetermined. This study aimed to investigate the optimal timing and cutoff value to ascertain the value of NPM1 mutation in MRD assessment. NPM1-mutated MRD was quantified by real-time polymerase chain reaction of bone marrow samples from 56 patients with NPM1-positive AML who achieved hematological remission. The area under the receiver-operating characteristic curve was greatest when MRD was assessed after two courses of post-remission therapy with a cutoff value of 0.010% (specificity, 68.4%; sensitivity, 87.0%). Patients whose MRD was below the cutoff value throughout the course of treatment had significantly better overall survival and relapse-free survival rates. Of the 33 patients who did not undergo transplantation during the first remission, all of the 11 who were never MRD-negative at any point experienced a relapse. Evaluating MRD with a cutoff value of 0.010% after two courses of post-remission therapy helps predict prognosis and determine the indication for allo-HSCT.

Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia.

Mutations of CCAAT/enhancer-binding protein alpha (CEBPAmu) are found in 10% to 15% of de novo acute myeloid leukemia (AML) cases. Double-mutated CEBPA (CEBPAdm) is associated with a favorable prognosis; however, single-mutated CEBPA (CEBPAsm) does not seem to improve prognosis. We investigated CEBPAmu for prognosis in 1028 patients with AML, registered in the Multi-center Collaborative Program for Gene Sequencing of Japanese AML. It was found that CEBPAmu in the basic leucine zipper domain (bZIP) was strongly associated with a favorable prognosis, but CEBPAmu out of the bZIP domain was not. The presence of CEBPAmu in bZIP was a strong indicator of a higher chance of achieving complete remission (P < .001), better overall survival (OS; P < .001) and a lower risk of relapse (P < .001). The prognostic significance of CEBPAmu in bZIP was also observed in the subgroup with CEBPAsm (all patients: OS, P = .008; the cumulative incidence of relapse, P = .063; patients aged ≤70 years and with intermediate-risk karyotype: OS, P = .008; cumulative incidence of relapse, P = .026). Multivariate analysis of 744 patients aged ≤70 years showed that CEBPAmu in bZIP was the most potent predictor of OS (hazard ratio, 0.3287; P < .001). CEBPAdm was validated as a cofounding factor, which was overlapping with CEBPAmu in bZIP. In summary, these findings indicate that CEBPAmu in bZIP is a potent marker for AML prognosis. It holds potential in the refinement of treatment stratification and the development of targeted therapeutic approaches in CEBPA-mutated AML.

Case-specific three-dimensional hologram with a mixed reality technique for tumor resection in otolaryngology.

OBJECTIVE: We report our first experience of using a case-specific three-dimensional (3D) hologram for tumor resection in otolaryngology to show the proof of concept. In addition, a questionnaire was administered to assess the usefulness of the mixed reality technique in otolaryngology. METHODS: A case-specific 3D hologram was developed from enhanced images of dynamic computed tomography, with reference to contrast-enhanced magnetic resonance images, and used for preoperative planning and intraoperative image reference. To evaluate the usefulness of the 3D hologram with head mount displays (HMDs), 18 attendings and resident otolaryngologists completed a questionnaire with the Likert scale. RESULTS: The case-specific 3D hologram on HMDs was successfully used by means of easy gesture-handling without any monitors preoperatively and intraoperatively. The experience of picturing the tumor localization and evaluating the surgical approach was statistically better using the 3D hologram on HMDs than using the computer images (P < .01). Similarly, the holograms were observed to be better for intraoperative application and surgical education than computer images (P < .01). CONCLUSION: We demonstrated the use of a case-specific 3D hologram for tumor resection in otolaryngology. The technology may be useful for preoperative planning and intraoperative image reference, especially for challenging cases, and surgical education. LEVEL OF EVIDENCE: NA.

Thermo- and Photoresponsive Behaviors of Dual-Stimuli-Responsive Organogels Consisting of Homopolymers of Coumarin-Containing Methacrylate.

Coumarin-containing vinyl homopolymers, such as poly(7-methacryloyloxycoumarin) (P1a) and poly(7-(2'-methacryloyloxyethoxy)coumarin) (P1b), show a lower critical solution temperature (LCST) in chloroform, which can be controlled by the [2 + 2] photochemical cycloaddition of the coumarin moiety, and they are recognized as monofunctional dual-stimuli-responsive polymers. A single functional group of monofunctional dual-stimuli-responsive polymers responds to dual stimuli and can be introduced more uniformly and densely than those of dual-functional dual-stimuli-responsive polymers. In this study, considering a wide range of applications, organogels consisting of P1a and P1b, i.e., P1a-gel and P1b-gel, respectively, were synthesized, and their thermo- and photoresponsive behaviors in chloroform were investigated in detail. P1a-gel and P1b-gel in a swollen state (transparent) exhibited phase separation (turbid) through a temperature jump and reached a shrunken state (transparent), i.e., an equilibrium state, over time. Moreover, the equilibrium degree of swelling decreased non-linearly with increasing temperature. Furthermore, different thermoresponsive sites were photopatterned on the organogel through the photodimerization of the coumarin unit. The organogels consisting of homopolymers of coumarin-containing methacrylate exhibited unique thermo- and photoresponsivities and behaved as monofunctional dual-stimuli-responsive organogels.

The EUTOS long-term survival score predicts disease-specific mortality and molecular responses among patients with chronic myeloid leukemia in a practice-based cohort.

The European Treatment and Outcome Study (EUTOS) long-term survival (ELTS) score predicts disease-specific death in patients with chronic myeloid leukemia (CML) being treated with imatinib during the chronic phase (CP) of the disease. However, it is unclear whether the ELTS score predicts CML-related events or treatment responses. This study evaluated the predictive value of the ELTS score regarding prognosis and treatment response in patients with CML-CP. Clinical data were retrospectively obtained from patients enrolled in the CML Cooperative Study Group (CML-CSG), which included patients diagnosed with CML-CP from April 2001 to January 2016, and treated with any tyrosine kinase inhibitor (TKI) as first-line therapy. Among 342 eligible patients, the ELTS scores indicated low-, intermediate-, and high-risk in 74%, 21%, and 5% of patients, respectively. Patients with high ELTS scores had significantly higher disease-specific mortality and worse event-free survival, progression-free survival, and overall survival. Among four risk scores, including the Sokal, Hasford, EUTOS, and ELTS scores, risk stratification by the ELTS score had the highest predictive value in assessing patient prognosis, and also in treatment responses. In fact, the EUTOS and ELTS scores were able to predict the major molecular response within 12 months. Most importantly, the ELTS score was the only scoring system that predicted deep molecular response at any time, regardless of risk level (65.0%, 43.7%, and 23.5% in low-, intermediate-, and high-risk groups, respectively). Compared to other risk scores, the ELTS score was the most sensitive risk classification tool for the four endpoints of interest in this study, as well as molecular responses in patients with CML-CP.

Development of proficiency-based knot-tying and suturing curriculum for otolaryngology residents: A pilot study.

OBJECTIVE: Basic surgical skills such as knot-tying and suturing are important for all otolaryngologists, regardless of subspecialty. The present study was undertaken in order to assess basic surgical techniques such as knot-tying and suturing required for novice otolaryngology residents with taking the variety of subspecialties into consideration, and evaluate the impact of a proficiency-based training curriculum based on these techniques. METHODS: A prospective study was performed for developing of proficiency-based knot-tying and suturing curriculum for otolaryngology residents in the third post-graduate year (PGY-3). The proficiency-based training curriculum was developed based on the tasks selected by RAND/UCLA method with expert panel, which is an iterative and anonymous survey used to establish consensus among participants. Expert panelists were selected from various divisions to reflect variety of their subspecialties. PGY-3 residents trained with the developed curriculum that included proctored pre-test, self-training to proficiency, and proctored post-test. Visual analogue scale (VAS) of trainees' overall competence in the operating room was self-assessed by each resident, before and after completing the training curriculum. RESULTS: Nine PGY-3 residents were enrolled as trainees. Eleven experts chosen as panelists had various subspecialty, including 2 from otology, 2 from rhinology, 2 from laryngology, 2 from head and neck surgery, and 3 from general otolaryngology. Seven tasks were selected from RAND/UCLA method and used to develop the curriculum. Trainee scores at pre-test were significantly lower than expert scores for all 7 tasks (p < 0.01) and each coefficient of variation of trainee score was larger than that of expert score (p < 0.05), supporting construct validity. The mean of composite scores between pre-test and post-test had statistical significance (68.6 ± 11.6 vs 95.9 ± 3.6, p < 0.01), documenting substantial improvement after training. Self-assessment VAS was also improved pre- to post-training (1.2 ± 0.9 vs 4.5 ± 1.4, p < 0.01). A follow-up questionnaire showed that trainees felt the educational curriculum to be beneficial. CONCLUSION: In the present study, seven basic technical skills were selected using the RAND/UCLA method and used to create a proficiency-based training curriculum. Our results indicate that this curriculum significantly improves proficiency of basic surgical skills of junior otolaryngology residents.

Potential role for second­generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia harboring additional clonal chromosome abnormalities: A retrospective CML Cooperative Study Group analysis.

Tyrosine kinase inhibitor (TKI) treatment is the standard of care for patients with chronic myeloid leukemia (CML). Even in the imatinib era, the presence of 'clonal chromosomal abnormalities' in the Philadelphia chromosome (CCA/Ph+) at diagnosis reportedly increased the risk of disease progression and predicted shorter survival. However, it remains unclear whether CCA/Ph+ is a poor prognostic marker in the era of new­generation TKIs. The data of patients with CML in the chronic phase (CP) that were extracted from the CML Cooperative Study Group database were retrospectively analyzed. Of the 328 eligible patients, 33 (10.1%) had CCA/Ph+, including 9 major route and 24 minor route aberrations. The characteristics of patients with and without CCA/Ph+ were similar; however, the proportion of blasts was higher among patients with CCA/Ph+. Notably, the survival rate of patients with CCA/Ph+ was not inferior to that of patients without CCA/Ph+, and there were no differences in responses to TKIs. All 9 patients with major route CCA/Ph+ attained a major molecular response (MMR) with no disease progression, and 8 ultimately achieved a deep molecular response. In particular, the median interval between TKI initiation and achievement of MMR was shorter in patients initially treated with a second­generation TKI than in those treated with imatinib (5 vs. 10 months). The present retrospective study, thus, revealed favorable treatment outcomes in CML­CP patients with CCA/Ph+ treated with second­generation TKIs. The data indicated that administering second­generation TKIs as first­line treatments is preferable in CML­CP patients with CCA/Ph+.

Retrospective Analysis of 20 Patients with DLBCL Who Received MCVAC Followed by Autologous Peripheral Blood Stem Cell Transplantation.

Autologous peripheral blood stem cell transplantation(auto-PBSCT)combined with high-dose chemotherapy has been considered as the standard therapy for relapsed or induction therapy-refractory aggressive lymphomas sensitive to chemotherapy. While various regimens have been applied as the conditioning,none has yet been established as the standard. We have begun to employ high-dose ranimustine,cytarabine,etoposide and cyclophosphamide(MCVAC)regimen. The present study was undertaken to review the efficacy and safety of MCVAC. Regimen: We carried out a retrospective analysis of 20 patients diagnosed as diffuse large B-cell lymphoma. The median follow-up duration of 20 patients was 13.05 months(range, 0.57-49.5 months). The 4-year OS and PFS were 57.8% and 30.2%,respectively. Relapse was the most frequent cause of treatment failure(n=7). The major toxicities were anorexia/nausea(95%),diarrhea (75%),hypokalemia (70%). One patient died of hepatic veno-occlusive disease(VOD). The serious adverse events included hypokalemia,arrhythmia,cerebral hemorrhage,and heart failure(1 case[5%]each). There was 1 case of a late-onset adverse event: therapy-related myelo- dysplastic syndrome/acute myeloblastic leukemia(MDS/AML). MCVAC regimen was concluded as effective and well-toler- ated. However,we should carefully monitored for the possible development of VOD and MDS/AML. Further follow-up is needed to evaluate the long-term efficacy and safety.

Vitamin B6 deficiency is prevalent in primary and secondary myelofibrosis patients.

Vitamin B6 (VB6) deficiency contributes to oncogenesis and tumor progression in certain cancers, and is prevalent in cancer patients in general. VB6 is also an essential element of heme synthesis, and deficiency can lead to anemia. Primary myelofibrosis (PMF) and secondary myelofibrosis (sMF) are myeloproliferative neoplasms often presenting with anemia along with other cytopenias. We performed a prospective study to determine whether PMF and sMF patients suffer from VB6 deficiency, and whether VB6-deficient patients show improvement of anemias with VB6 supplementation. Twelve PMF patients and 11 sMF patients were analyzed. A total of 16 of 23 patients (69.6%) were found to have VB6 deficiency, but VB6 supplementation with pyridoxal phosphate hydrate did not elevate hemoglobin levels in deficient patients. None of the patients presented with vitamin B12, iron, or copper deficiencies. Four patients showed serum folate levels below the lower limit of normal and eight patients showed serum zinc levels below the lower limit of normal; however, these deficiencies were marginal and unlikely to contribute to anemia. Compared to VB6-sufficient patients, VB6-deficient patients showed significantly lower serum folate levels and higher serum copper levels. Studies elucidating the relationship of VB6 deficiency and etiology of PMF/sMF are warranted.

Study on Control of pH-Modulation Crystallization Utilizing Concept of Dissociation Equilibrium.

Crystallization by pH adjustment, as a type of reaction crystallization, is a solid-liquid separation method widely used in the area of pharmaceutical and pharmaceutical intermediate manufacturing. On the other hand, 3-alkenyl cephem compound is a typical zwitterionic pharmaceutical intermediate that possesses both an amino group and a carboxylic acid group. Such structure affords three main pH regions in solution and results in difficulties using crystallization by pH adjustment for isolation. As a consequence, 3-alkenyl cephem compound is usually crystallized at the point away from the solubility curve, causing unrestricted nucleation and flocculation behavior for the deposited particles which is difficult to filtrate. In this study, the pKa of 3-alkenyl cephem compound was intensively investigated to inhibit the nucleation. An optimal pH level point was also sought to make monodisperse particles. In particular, during crystallization by pH-modulation operation, the key point was identified to be the number of primary particles aggregated in the secondary particles. It was revealed that the increment number of primary particles led to the generation of larger monodisperse particles. This investigation, combined with solid-liquid equilibrium, enabled the acquisition of target species with good operability for filtration process. This present investigation becomes the prosperity in the zwitterion compound production that it has hardships to crystallize and filtrate.