Chapter 3: Management of kidney injury caused by cancer drug therapy, from clinical practice guidelines for the management of kidney injury during anticancer drug therapy 2022.

Cisplatin should be administered with diuretics and Magnesium supplementation under adequate hydration to avoid renal impairment. Patients should be evaluated for eGFR (estimated glomerular filtration rate) during the treatment with pemetrexed, as kidney injury has been reported. Pemetrexed should be administered with caution in patients with a CCr (creatinine clearance) < 45 mL/min. Mesna is used to prevent hemorrhagic cystitis in patients receiving ifosfamide. Febuxostat is effective in avoiding hyperuricemia induced by TLS (tumor lysis syndrome). Preventative rasburicase is recommended in high-risk cases of TLS. Thrombotic microangiopathy could be triggered by anticancer drugs and there is no evidence of efficacy of plasma exchange therapy. When proteinuria occurs during treatment with anti-angiogenic agents or multi-kinase inhibitors, dose reductions or interruptions based on grading should be considered. Grade 3 proteinuria and renal dysfunction require urgent intervention, including drug interruption or withdrawal, and referral to a nephrologist should be considered. The first-line drugs used for blood pressure elevation due to anti-angiogenic agents are ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin receptor blockers). The protein binding of drugs and their pharmacokinetics are considerably altered in patients with hypoalbuminemia. The clearance of rituximab is increased in patients with proteinuria, and the correlation with urinary IgG suggests similar pharmacokinetic changes when using other antibody drugs. AIN (acute interstitial nephritis) is the most common cause of ICI (immune checkpoint inhibitor)-related kidney injury that is often treated with steroids. The need for renal biopsy in patients with kidney injury that occurs during treatment with ICI remains controversial.

Association between adjunct clindamycin and in-hospital mortality in patients with necrotizing soft tissue infection due to group A Streptococcus: a nationwide cohort study.

Necrotizing soft tissue infection (NSTI) due to group A Streptococcus (GAS) is a severe life-threatening microbial infection. The administration of adjunct clindamycin has been recommended in the treatment of NSTIs due to GAS. However, robust evidence regarding the clinical benefits of adjunct clindamycin in NSTI patients remains controversial. We aimed to investigate the association between early administration of adjunct clindamycin and in-hospital mortality in patients with NSTI attributed to GAS. The present study was a nationwide retrospective cohort study, using the Japanese Diagnosis Procedure Combination inpatient database focusing on the period between 2010 and 2018. Data was extracted on patients diagnosed with NSTI due to GAS. We compared patients who were administered clindamycin on the day of admission (clindamycin group) with those who were not (control group). A propensity score overlap weighting method was adopted to adjust the unbalanced backgrounds. The primary endpoint was in-hospital mortality and survival at 90 days after admission. We identified 404 eligible patients during the study period. After adjustment, patients in the clindamycin group were not significantly associated with reduced in-hospital mortality (19.2% vs. 17.5%; odds ratio, 1.11; 95% confidence interval, 0.59-2.09; p = 0.74) or improved survival at 90 days after admission (hazard ratio, 0.92; 95% confidence interval, 0.51-1.68; p = 0.80). In this retrospective study, early adjunct clindamycin does not appear to improve survival. Therefore, the present study questions the benefits of clindamycin as an adjunct to broad spectrum antibiotics in patients with NSTI due to GAS.

Breath-by-breath P0.1 measured on quasi-occlusion via Hamilton C6 may result in underestimation of respiratory drive and inspiratory effort.

We aimed to identify the threshold for P0.1 in a breath-by-breath manner measured by the Hamilton C6 on quasi-occlusion for high respiratory drive and inspiratory effort. In this prospective observational study, we analyzed the relationships between airway P0.1 on quasi-occlusion and esophageal pressure (esophageal P0.1 and esophageal pressure swing). We also conducted a linear regression analysis and derived the threshold of airway P0.1 on quasi-occlusion for high respiratory drive and inspiratory effort. We found that airway P0.1 measured on quasi-occlusion had a strong positive correlation with esophageal P0.1 measured on quasi-occlusion and esophageal pressure swing, respectively. Additionally, the P0.1 threshold for high respiratory drive and inspiratory effort were calculated at approximately 1.0 cmH2O from the regression equations. Our calculations suggest a lower threshold of airway P0.1 measured by the Hamilton C6 on quasi-occlusion than that which has been previously reported.

On-site placement of resuscitative endovascular balloon occlusion of the aorta (REBOA) in a hemorrhagic shock patient: A successful endeavor involving long-distance air transport.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is primarily utilized in traumatic non-compressible torso hemorrhage. We present a 49-year-old male with hemorrhagic shock necessitating on-site REBOA placement on an island 986 km away from the nearest critical care center. The patient experienced sudden pain in the right costal margin and visited the local clinic where computed tomography revealed a massive intra-abdominal hemorrhage and a renal artery aneurysm. An emergency care physician was deployed via fixed-wing aircraft who positioned the REBOA on-site in the thoracic aorta. Partial balloon inflation (partial REBOA) and intermittent inflation/deflation (intermittent REBOA) was repeated throughout the 5-h return flight. Despite prolonged REBOA placement, no safety issues or ischemic complications were documented and parent artery occlusion was subsequently performed via interventional radiology at our facility. The patient was later discharged home in a good state of health. On-site REBOA placement is not only applicable to trauma but also internal hemorrhaging due to non-traumatic causes. Partial and intermittent REBOA successfully stabilized circulation, prevented organ ischemia and facilitated long-distance patient transport in the present case.

Prevalence of thromboembolic events and status of prophylactic anticoagulant therapy in hospitalized patients with COVID-19 in Japan.

INTRODUCTION: One of the most prominent and concerning complications associated with coronavirus disease 2019 (COVID-19) is venous and arterial thromboembolisms. The aim of the present study was to delineate the prevalence of thromboembolic events and the current status of prophylactic anticoagulation therapy in patients with COVID-19 in Japan. METHODS: Between February 1 and August 31, 2020, we performed a dual-center, retrospective cohort study based on data obtained from the medical charts of COVID-19 patients admitted to healthcare facilities in Japan. The primary outcome was any thromboembolic event including pulmonary embolism (PE), deep vein thrombosis (DVT), myocardial infarction, ischemic stroke and other systemic thromboemboli. RESULTS: During the study period, we extracted 628 consecutive patients admitted for COVID-19. Prophylactic anticoagulant therapy was administered in 63 (10%) patients of whom 20 (31.7%) were admitted to the intensive care unit (ICU). Thromboembolic events occurred in 18 (2.9%) patients (14.3% of patients in ICU and 2.2% of patients in the general wards). DVT were detected in 13 (2.1%) patients, PE in 11 (1.8%), and both DVT and PE in 6 (0.96%) patients. An increasing prevalence in thromboembolic events was noted with progressive clinical severity. Overall in-hospital mortality was 4.8%. CONCLUSIONS: Prophylactic anticoagulation therapy was administered in only 10% of all hospitalized COVID-19 patients. The prevalence of any thromboembolic events was 2.9% in COVID-19 patients with most events occurring in severe and critical patients. Therefore, prophylactic anticoagulation therapy may be warranted in severe and critical patients but in asymptomatic to moderate patients the practice remains controversial.

A comparison on the percentage of polymerase chain reaction positivity for SARS-CoV-2 between Public Health Center referrals and direct walk-in patients: A single center retrospective analysis in Tokyo.

INTRODUCTION: The Public Health Center (PHC)-known as hokenjo in Japan-assume a crucial role in disease control. Coronavirus disease 2019 (COVID-19) is one of many designated infectious diseases monitored by the agency. During the present pandemic, patients who suspected COVID-19 were instructed to call the Coronavirus Consultation Center in the PHC prior to visiting the hospital. The aim of this study was to elucidate the differences in polymerase chain reaction (PCR) positivity between PHC referrals and direct walk-in patients. METHODS: The present was a single-center, retrospective cohort study conducted at the Tokyo Metropolitan Hospital from March to September, 2020. Patients who received a PCR test for SARS-CoV-2 were included and categorized into the PHC referral or direct walk-in groups. The outcomes included the total number of patients undergoing PCR tests and the percentage of PCR positivity in each group. RESULTS: We identified 1680 patients (781 PHC referred and 899 direct walk-in groups). The percentage of PCR positivity did not significantly differ between the PHC referral and direct walk-in groups during the first wave (30.5% vs. 29.2%; p = 0.78). PCR positivity was significantly higher in the PHC referral group than the direct walk-in group during the second wave (30.1% vs. 23.1%; p = 0.051) and entire study period (30.2% vs. 24.7%; p = 0.011). CONCLUSIONS: Despite health authority recommendations, the number of direct walk-in patients were higher than PHC referral patients. The percentage of PCR positivity was significantly higher in the PHC referral group than in the direct walk-in group.

Effect of high-dose vitamin C therapy on severe burn patients: a nationwide cohort study.

BACKGROUND: Vitamin C is a well-documented antioxidant that reduces oxidative stress and fluid infusion in high doses; however, the association between high-dose vitamin C and reduced mortality remains unclear. This study evaluates the effect of high-dose vitamin C in severe burn patients under two varying thresholds. METHODS: We enrolled adult patients with severe burns (burn index ≥ 15) who were registered in the Japanese Diagnosis Procedure Combination national inpatient database from 2010 to 2016. Propensity score matching was performed between patients who received high-dose vitamin C within 1 day of admission (vitamin C group) and those who did not (control group). High-dose vitamin C was defined as a dosage in excess of 10 g or 24 g within 2 days of admission. The primary outcome was in-hospital mortality. RESULTS: Eligible patients (n = 2713) were categorized into the vitamin C group (n = 157) or control group (n = 2556). After 1:4 propensity score matching, we compared 157 and 628 patients who were administered high-dose vitamin C (> 10-g threshold) and controls, respectively. Under this particular threshold, high-dose vitamin C therapy was associated with reduced in-hospital mortality (risk ratio, 0.79; 95% confidence interval, 0.66-0.95; p = 0.006). In contrast, in-hospital mortality did not differ between the control and high-dose vitamin C group under the > 24-g threshold (risk ratio, 0.83; 95% confidence interval, 0.68-1.02; p = 0.068). CONCLUSIONS: High-dose vitamin C therapy was associated with reduced mortality in patients with severe burns when used under a minimum threshold of 10 g within the first 2 days of admission. While "high-dose" vitamin C therapy lacks a universal definition, the present study reveals that different "high-dose" regimens may yield improved outcomes.

Body temperature change and outcomes in patients undergoing long-distance air medical transport.

BACKGROUND: Short-distance air medical transport for adult emergency patients does not significantly affect patients' body temperature and outcomes. This study aimed to examine the influence of long-distance air medical transport on patients' body temperatures and the relationship between body temperature change and mortality. METHODS: We retrospectively enrolled consecutive patients transferred via helicopter or plane from isolated islands to an emergency medical center in Tokyo, Japan between April 2010 and December 2016. Patients' average body temperature was compared before and after air transport using a paired t-test, and corrections between body temperature change and flight duration were calculated using Pearson's correlation coefficient. Multivariable logistic regression models were then used to examine the association between body temperature change and in-hospital mortality. RESULTS: Of 1253 patients, the median age was 72 years (interquartile range, 60-82 years) and median flight duration was 71 min (interquartile range, 54-93 min). In-hospital mortality was 8.5%, and average body temperature was significantly different before and after air transport (36.7 °C versus 36.3 °C; difference: -0.36 °C; 95% confidence interval, -0.30 to -0.42; p < 0.001). There was no correlation between body temperature change and flight duration (r = 0.025, p = 0.371). In-hospital death was significantly associated with (i) hyperthermia (>38.0 °C) or normothermia (36.0-37.9 °C) before air transport and hypothermia after air transport (odds ratio, 2.08; 95% confidence interval, 1.20-3.63; p = 0.009), and (ii) winter season (odds ratio, 2.15; 95% confidence interval, 1.08-4.27; p = 0.030). CONCLUSION: Physicians should consider body temperature change during long-distance air transport in patients with not only hypothermia but also normothermia or hyperthermia before air transport, especially in winter.

[Diaphragmatic Injury Due to Blunt Trauma Diagnosed by a Diagnostic Thoracoscopy;Report of a Case].

We performed an exploratory thoracoscopy for a suspected diaphragm injury caused by a blunt-force chest trauma. A male patient in his fifties involved in a traffic accident and was transported by ambulance to our hospital. Upon arrival, his vital signs were stable, however, he was diagnosed as having fractures of the right tibia and fibula, multiple rib fractures and a slight right hemothorax. The limb fracture was treated by emergency surgery and the chest trauma was managed by chest drainage. Since injury of the diaphragm by fragment of the right 10th rib was suspected with chest computed tomography(CT), an exploratory thoracoscopy was performed after orthopedic surgery, and a laceration of the diaphragm without herniation was successfully closed.

Fulminant type 1 diabetes mellitus with remarkable elevation of serum pancreatic enzymes.

Fulminant type 1 diabetes mellitus progresses extremely rapidly and is accompanied by ketoacidosis. Patients with the disease present at emergency departments with non-specific symptoms, including fever, nausea, vomiting, and abdominal pain. Here, we present a case of fulminant type 1 diabetes mellitus where the patient was initially misdiagnosed with gastroenteritis and acute pancreatitis. A 50-year-old Japanese woman was referred to our hospital with coma and shock. She had presented with nausea, vomiting, abdominal pain and thirst from 5 days before admission, and had been misdiagnosed with gastroenteritis by her primary care physician. Upon examination, metabolic acidosis and remarkable elevation of pancreatic exocrine enzymes were found (amylase 4322 IU/L, lipase 1046 IU/L). Acute pancreatitis was initially suspected because of the high pancreatic enzyme levels and abdominal pain. However, her plasma glucose level was markedly elevated at 1357 mg/dL. The patient was diagnosed with fulminant type 1 diabetes mellitus. Computed tomography showed no radiological evidence of acute pancreatitis. In conclusion, fulminant type 1 diabetes mellitus is often referred to hospital with flu-like or gastrointestinal symptoms and elevation of serum pancreatic enzymes. Physicians must be sure not to misdiagnose it as gastroenteritis or acute pancreatitis.

NANOG Expression as a Responsive Biomarker during Treatment with Hedgehog Signal Inhibitor in Acute Myeloid Leukemia.

Aberrant activation of the Hedgehog (Hh) signaling pathway is involved in the maintenance of leukemic stem cell (LSCs) populations. PF-0444913 (PF-913) is a novel inhibitor that selectively targets Smoothened (SMO), which regulates the Hh pathway. Treatment with PF-913 has shown promising results in an early phase study of acute myeloid leukemia (AML). However, a detailed mode of action for PF-913 and relevant biomarkers remain to be elucidated. In this study, we examined bone marrow samples derived from AML patients under PF-913 monotherapy. Gene set enrichment analysis (GSEA) revealed that PF-913 treatment affected the self-renewal signature and cell-cycle regulation associated with LSC-like properties. We then focused on the expression of a pluripotency factor, NANOG, because previous reports showed that a downstream effector in the Hh pathway, GLI, directly binds to the NANOG promoter and that the GLI-NANOG axis promotes stemness and growth in several cancers. In this study, we found that a change in NANOG transcripts was closely associated with GLI-target genes and NANOG transcripts can be a responsive biomarker during PF-913 therapy. Additionally, the treatment of AML with PF-913 holds promise, possibly through inducing quiescent leukemia stem cells toward cell cycling.

Comparison of Sapwood Discoloration in Fagaceae Trees After Inoculation with Isolates of Raffaelea quercivora, Cause of Mass Mortality of Japanese Oak Trees.

The mass mortality of oak trees has been prevalent in Japan since the late 1980s. The fungus Raffaelea quercivora is transmitted by an ambrosia beetle, Platypus quercivorus, which causes mortality. The beetle is able to bore galleries into the sapwood of most Fagaceae trees in Japan; however, the level of mortality caused by R. quercivora and P. quercivorus differs greatly among tree species. Previous studies by our research group have demonstrated that the virulence of R. quercivora differs among isolates when inoculated into Quercus serrata logs. However, interactions between the virulence of R. quercivora isolates and the susceptibility of other fagaceous species have yet to be elucidated. In this study, we inoculated the fresh logs of 11 fagaceous species with isolates of low and high virulence, and measured the tangential widths of discolored sapwoods 3 weeks after inoculation. Although the discoloration widths of Q. crispula sapwood were similar among all isolates, those of Q. serrata and Q. acutissima tended to increase with the more virulent isolates. Sapwood discoloration in Q. glauca, Q. acuta, Q. salicina, Lethocarpus edulis, and Castanopsis sieboldii was greatly increased by highly virulent isolates. Discoloration in Fagus japonica was not influenced by any of the isolates. The logs of Q. crispula and Q. serrata but not Q. glauca were significantly more discolored by a low-virulence isolate compared with standing trees. The various virulent isolates induced unique sapwood discoloration characteristics in each species, which may explain species-specific differences in mortality rates.

[Clinical analysis of delayed hemothorax due to diaphragmatic injury treated by emergent video-assisted thoracic surgery].

We encountered 5 cases of delayed massive hemothorax due to diaphragmatic injury. Delayed hemothorax presented 2∼11 days after injury, with lower rib fractures seen all cases. We performed emergent video-assisted thoracic surgery with mini-thoracotomy for all patients. Lacerations could be clearly visualized in the diaphragm after evacuation of blood clots, which were then sutured. In four cases, the sharp edges of the broken ribs were thought to have caused the diaphragmatic lacerations. The mean blood loss volume was 2,905 ml, and all patients required blood transfusions. However, homeostasis was achieved after surgery, and all patients had an uneventful postoperative course. Although, delayed hemothorax is relatively uncommon, it needs to be considered a lethal condition.

Optimal index for detecting splenic involvement on 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging in diffuse large B-cell lymphoma.

Accurate clinical staging is important in diffuse large B-cell lymphoma (DLBCL) to adapt to optimal therapy. Splenic involvement of DLBCL has been recently more detectable with the advancement of a diagnostic scan by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT). Our clinical question is whether splenic involvement was adequately diagnosed by FDG-PET/CT imaging. This retrospective study aimed to determine the optimal index for evaluating splenic involvement in patients with DLBCL. Patients with newly diagnosed DLBCL who were examined with FDG-PET/CT at diagnosis and the end of induction chemotherapy (EOI) was enrolled. The splenic involvement with the splenic FDG uptake value higher than that of the liver at diagnosis or with the decrease of splenic uptake at EOI by visual evaluation was evaluated as positive. The calculative evaluation of splenic involvement, based on the data of standardized uptake value (SUV) of the spleen, used maximum SUV (SUVmax), mean SUV (SUVmean), spleen total lesion glycolysis (spleen TLG), and spleen length. A change in each index following induction chemotherapy was expressed as an index. Receiver operating characteristic analysis was used to set the cutoff value for each index. This study included 52 patients. Spleen TLG (0.904) showed the best accuracy, followed by SUVmax (0.885) and SUVmean (0.885), among the 5 indexes for splenic involvement at diagnosis. Splenic involvement was predicted with a higher accuracy level (0.923) when selecting the cases with values higher than the cutoff level on both spleen TLG and SUVmax. The decision at EOI was more suitable by selecting both positive cases of ∆ TLG and ∆ SUVmax. Obtaining both the positive spleen TLG and SUVmax is recommended at diagnosis to predict splenic involvement. The assessment by ∆ spleen TLG and ∆ SUVmax seems to be optimal.

Community structures of Mesostigmata, Prostigmata and Oribatida in broad-leaved regeneration forests and conifer plantations of various ages.

The community structures of Mesostigmata, Prostigmata, and Oribatida in the soil of broad-leaved regeneration forests and conifer plantations of various ages were assessed alongside soil and plant environmental variables using three response metrics (density, species richness, and species-abundance distribution). The density and species richness of mites recovered swiftly after clear-cutting or replanting. Oribatid mites dominated the soil mite communities in terms of densities and species richness for both forest types. Soil mite communities in broad-leaved forests was related to forest age, the crown tree communities index, and forest-floor litter weight. In contrast, soil mite communities in the conifer plantation sites were related to various indices of understory plants. The development of the understory plants was synchronized with the silvicultural schedules, including a closed canopy and thinning. Such a conifer plantation management may affect indirectly the community of mites.

Reintubation in COVID-19 patients: a multicenter observational study in Japan (J-RECOVER study).

BACKGROUND: Reintubation is not an uncommon occurrence following extubation and discontinuation of mechanical ventilation. In COVID-19 patients, the proportion of reintubation may be higher than that of non-COVID-19 patients. Furthermore, COVID-19 patients may have a higher risk for developing laryngotracheal stenosis, along with a higher proportion of reintubation than in non-COVID-19 patients. Our understanding of the proportion of reintubation in COVID-19 patients is limited in Japan. Additionally, the reasons for reintubation have not been adequately examined in previous studies outside of Japan. Thus, the present study aimed to describe the proportion and causes of reintubation among COVID-19 patients in Japan. METHODS: This was a multicenter observational study that included 64 participating centers across Japan. This study included mechanically ventilated COVID-19 patients who were discharged between April 1, 2020 and September 30, 2020. The outcomes examined were the proportion and causes of reintubation. RESULTS: A total of 373 patients were eligible for inclusion in the current analysis. The median age of patients was 64 years and 80.4% were male. Reintubation was required for 35 patients (9.4%) and the most common causes for reintubation were respiratory failure (71.4%; n = 25) and laryngotracheal stenosis (8.6%; n = 3). CONCLUSIONS: The proportion of reintubation among COVID-19 patients in Japan was relatively low. Respiratory failure was the most common cause for reintubation. Reintubation due to laryngotracheal stenosis accounted for only a small fraction of all reintubated COVID-19 patients in Japan.

A Pathogenic NRAS c.38G>A (p.G13D) Mutation in RARA Translocation-negative Acute Promyelocytic-like Leukemia with Concomitant Myelodysplastic Syndrome.

An acute promyelocytic leukemia (APL) patient not demonstrating the retinoic acid receptor α (RARA) translocation is rare. A 76-year-old man was diagnosed with myelodysplastic syndrome (MDS). After a year, abnormal promyelocytes were detected with pancytopenia and disseminated intravascular coagulopathy. Morphologically, the patient was diagnosed with APL; however, a genetic examination failed to detect RARA translocation. Thereafter, whole-genome sequencing revealed an NRAS missense mutation [c.38G>A (p.G13D)]. This mutation was not detected in posttreatment bone marrow aspirate, despite residual MDS. Few reports are available on similar cases. Furthermore, the NRAS c.38G>A mutation may be a novel pathogenic variant exacerbating RARA translocation-negative acute promyelocytic-like leukemia.

Unexpected appearance of KMT2A::MLLT10 fusion transcript in acute myeloid leukemia with t(5;11)(q31;q23.3).

As an uncommon but nonrandom translocation in acute myeloid leukemia (AML) t(5;11)(q31;q23) results in fusion between KMT2A at 11q23 and ARHGAP26 at 5q31. The 5q31 region has another KMT2A partner, AFF4, which was identified in acute lymphoblastic leukemia harboring ins(5;11)(q31;q13q23). We report here a 65-year-old woman with AML M5b. G-banding and spectral karyotyping demonstrated 46,XX,t(5;11)(q31;q23.3). Fluorescence in situ hybridization revealed not only separated 5' and 3' KMT2A signals but a faint 5' KMT2A signal. Reverse transcription polymerase chain reaction (RT-PCR), using a KMT2A sense primer and ARHGAP26 antisense primer, detected no band whereas RT-PCR with a AFF4 antisense primer revealed an amplified band. However, sequence analysis unexpectedly disclosed that KMT2A exon 6 was connected with MLLT10 exons 15 to 18. This may be due to cross-hybridization between MLLT10 exon 18 and AFF4 antisense primer derived from AFF4 exon 10 since both exons had eight identical bases (AAGCAGCT). The MLLT10 gene is located at 10p12.31; a faint 5' KMT2A signal was probably present at this locus. These findings indicate that in AML the 5' KMT2A fragment containing exons 1 to 6 may be cryptically inserted into MLLT10 intron 14 when a reciprocal translocation t(5;11)(q31;q23.3) involving KMT2A occurred.

GSK3 inhibitor enhances gemtuzumab ozogamicin-induced apoptosis in primary human leukemia cells by overcoming multiple mechanisms of resistance.

In acute myeloid leukemia (AML), the heterogeneity of genetic and epigenetic characteristics makes treatment difficult. The prognosis for AML is therefore poor, and there is an urgent need for new treatments for this condition. Gemtuzumab ozogamicin (GO), the first antibody-drug conjugate (ADC), targets the CD33 antigen expressed in over 90% of AML cases. GO therefore has the potential to counter the heterogeneity of AML patients. However, a major clinical problem is that drug resistance to GO diminishes its effect over time. Here, we report that the inhibition of glycogen synthase kinase 3 (GSK3) alone overcomes several forms of GO resistance at concentrations without antileukemic effects. The GSK3 inhibitors tested significantly enhanced the cytotoxic effect of GO in AML cell lines. We elucidated four mechanisms of enhancement: (1) increased expression of CD33, the target antigen of GO; (2) activation of a lysosomal function essential for hydrolysis of the GO linker; (3) reduced expression of MDR1 that eliminates calicheamicin, the payload of GO; and (4) reduced expression of the anti-apoptotic factor Bcl-2. A similar combination effect was observed against patient-derived primary AML cells. Combining GO with GSK3 inhibitors may be efficacious in treating heterogeneous AML.

Safety and Accuracy of Professional Continuous Glucose Monitoring in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Hyperglycemia in the early days following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-known risk factor for acute graft-versus-host disease (GVHD) and non-relapse mortality. The FreeStyle Libre Pro, a factory calibrated continuous glucose monitoring (CGM) device, has been used for the retrospective analysis of glucose testing in patients with diabetes. We assessed the safety and accuracy of the device in patients undergoing allo-HSCT. We recruited eight patients who underwent allo-HSCT between August 2017 and March 2020. They wore the FreeStyle Libre Pro on the day before or on the day of transplantation until 28 days after transplantation. Adverse events, especially bleeding and infection, were monitored to assess safety, and blood glucose levels were measured and compared with the device values. None of the eight participants experienced bleeding that was difficult to stop from the sensor site or local infection that required antimicrobial administration. The device value was well correlated with blood glucose (correlation coefficient r=0.795, P<0.01); however, the overall mean absolute relative difference was 32.1%±16.0%. Our study demonstrated the safety of FreeStyle Libre Pro in allo-HSCT patients. However, the sensor results tended to be lower than the blood glucose levels.