Faster surgery initiation in oral cancer patients during the COVID-19 pandemic in Osaka, Japan.

BACKGROUND: We investigated the impact of the COVID-19 pandemic on oral cancer (OC), comparing diagnosis and number of pre-operative days in the diagnosis of OC in 2019 (pre-COVID-19) and that in 2020 (during the COVID-19 pandemic). METHODS: Using data from a cancer registry-based study on the impact of COVID-19 on cancer care in Osaka (CanReCO), we collected details of sex, age, residential area, cancer site, date of diagnosis, clinical stage at first treatment and number of pre-operative days in OC patients. RESULTS: A total of 1470 OC cases were registered. Incidence of OC before and during COVID-19 was 814 and 656 cases, respectively. During the first wave of the pandemic (March to May 2020), incidence was about half that in the same period in 2019 (2019; n = 271, 2020; n = 145). Number of pre-operative days (median number of days between the first hospital visit and surgery date) was significantly shorter during the COVID-19 year (24.5 days) than in the pre-COVID-19 year (28 days, p = 0.0015). CONCLUSIONS: Incidence of OC during the COVID-19 pandemic was lower than in pre-COVID-19. Despite disruption in the healthcare system, the number of pre-operative days for OC cases was shorter during the pandemic.

Neurological impairment in children with acute liver failure following liver transplantation-A single-center experience.

BACKGROUND: Although overall survival of ALF has improved, neurological restoration after recovery from ALF may not always be satisfactory. The purpose of this study was to investigate the occurrence and possible causes of NI in children with ALF following LT. METHODS: We retrospectively examined all children younger than 16 years old with ALF who subsequently underwent LT at our center between January 2005 and December 2016. NI was assessed in December 2016 using the six-point Pediatric Cerebral Performance Category score and was defined as any increase in the score. RESULTS: There were 62 children with median age 10 months (quartile range 5-34). The etiology of ALF was indeterminate in 47 children (75.8%). The median duration from admission to LT was 5.5 days (quartile range 4-7), and 96.8% (60/62) received living donor LT. The overall survival was 83.9% (52/62) in a median follow-up period of 4.2 years. Mild-to-moderate NI was observed in 23.1% (12/52) of the survivors. Possible causes of NI were underlying systemic disease (n = 3), perioperative brain lesion (n = 2), and unclassified (n = 7). All seven patients with unclassified NI were less than 12 months old. The unclassified NI causes were presumed to be ALF, its perioperative care, and the vulnerable infant brain. CONCLUSIONS: NI in children with ALF following LT was not rare and should be prevented. Further investigations are required to clarify the characteristics of the patients with unclassified NI.

Hematological and biochemical characteristics and diagnostic imaging results in acute T cell-mediated rejection after pediatric liver transplantation.

BACKGROUND: Liver biopsy is the gold standard for diagnosing TCMR after LT. However, complications caused by liver biopsy may occur especially during the immediate post-transplantation period and other effective methods for predicting TCMR have not been established. Thus, we investigated whether hematological and biochemical characteristics and Doppler ultrasonography findings are associated with acute TCMR. METHODS: A multiple logistic regression analysis was performed to identify the prognostic factors of acute TCMR, defined as a RAI ≥4. Then, a ROC curve analysis was conducted to evaluate for diagnostic performance. The relationship between prognostic factors and each histological category of RAI was investigated. RESULTS: Eighty-nine liver biopsies were performed on 85 patients between January 2012 and December 2019. The RAI of 62 (69.7%) liver biopsies was ≥4. AEC (×104 /µl), direct bilirubin level (mg/dl), and MHVV (cm/s) were found to be associated with acute TCMR (OR: 4.96, 95% CI: 1.44-17.0, p = .011; OR: 1.41, 95% CI: 1.04-1.91, p = .025; OR: 1.05, 95% CI: 1.02-1.08, p < .001, respectively). The area under the ROC curves for predicting acute TCMR was 0.86 (95% CI: 0.78-0.94). There was a correlation between AEC, direct bilirubin level, and MHVV as well as the severity of RAI. CONCLUSIONS: AEC, direct bilirubin level, and MHVV were the independent risk factors for acute TCMR. This study could provide information regarding the identification of patients requiring liver biopsy.

Estimating the insertion length of pediatric peripherally inserted central catheters.

BACKGROUND: It is difficult to determine the insertion length of peripherally inserted central catheters (PICCs) without fluoroscopy. The objectives of this study were to examine the relationship between the length from the anterior axillary point to the level of the carina (Lcarina ) and patient's height, and to obtain possible estimation formulas that can be considered for validation in future studies. METHODS: We retrospectively analyzed PICCs from the upper arm in the pediatric intensive care unit (PICU) between May 2017 and September 2018. We evaluated the relationship between Lcarina and the patient's height using linear regression. We also conducted simulated performance assessment of simplified formulas based on the observed relationships. RESULTS: Fifty-four PICCs from the right arm and 49 from the left for patients at the median age of 1 year were analyzed. The following linear correlations between Lcarina and the patient's height were observed: 0.105 × height (cm) + 1.53 (cm) (P < 0.001, R2 = 0.71) from the right arm, and 0.125 × height (cm) + 1.21 (cm) (P < 0.001, R2 = 0.65) from the left arm. In the simulated performance assessment, with a simplified formula, [0.1 × height (cm) + 1 (cm)], 93% (50/54) of the PICCs from the right arm and 96% (47/49) from the left arm were expected to be inserted in the subclavian vein, innominate vein, or superior vena cava. CONCLUSIONS: The level of the carina was correlated with the patient's height. A simplified formula, 0.1 × height (cm) + 1, seemed to perform acceptably and appeared to be worth validating in future studies.

Plasma exchange and infliximab as a third-line therapy for refractory infantile Kawasaki disease.

BACKGROUND: The treatment for Kawasaki disease (KD) patients refractory to intravenous immunoglobulin (IVIG) therapy is still controversial, and the efficacy of plasma exchange (PE) and infliximab (IFX) therapy for infantile KD is unknown. METHODS: A total of 22 infantile KD patients refractory to initial and additional IVIG, who received either PE or IFX as third-line therapy from October 2008 to February 2020 were examined retrospectively. The patients' sex, age, days of first IVIG, days of PE or IFX therapy, laboratory data preceding PE or IFX therapy, coronary artery lesions (CALs), and adverse effects were investigated. RESULTS: Thirteen patients received PE and nine patients received IFX as the third-line therapy. For the median age at onset, the median days of first IVIG and PE or IFX, and pre-PE or IFX therapy blood test results, there were no significant between-group differences. At admission, and before and after the third-line therapy, there were also no significant differences in occurrence of CALs. The frequency of serious adverse events was significantly higher in the PE group than in the IFX group. CONCLUSIONS: Although there were no significant differences in patient background, blood test results, or frequency of CALs, the frequency of adverse events was significantly higher in the PE group. With the trend of expansion of IFX therapy for KD patients refractory to IVIG, the role of PE as the additional therapy may become more limited.

[New Attempt of Radiation Oncology Section to Radiotherapy for Head and Neck Cancer].

Oral care is important for patients with head and neck cancer who undergo radiotherapy because these patients encounter various symptoms, which decrease their quality of life(QOL). Oral mucositis is considered the major side effect of radiation, and the dose-volume parameters can serve as predictors of the occurrence of severe oral mucositis. Therefore, understanding radiation treatment planning(e. g., prescription dose and irradiated volumes of the organs at risk)and providing oral healthcare before, during, and after radiotherapy are essential for maintaining patients' QOL. METHODS: An RT viewer (Climb Medical Systems) was installed into the inhouse hospital information system to provide education regarding radiation treatment planning to medical staff members (dentists and nurses) by medical physicists. RESULTS: Patients can undertake appropriate oral care before radiotherapy, and this intervention has potential for reducing the radiation-related side effect. CONCLUSION: Education regarding radiation treatment planning by medical physicists using the RT viewer could improve the knowledge of medical staffs regarding the predictors of radiation-induced side effects for. By introducing the appropriate intervention of oral care before radiotherapy, it may be feasible to maintain patients' QOL.

Ultrasound-Guided Postpyloric Feeding Tube Placement in Critically Ill Pediatric Patients.

OBJECTIVES: Various methods to insert postpyloric feeding tubes at the bedside have been reported, but the optimal method remains controversial. The objective of this study was to evaluate the effect of ultrasound-guided postpyloric feeding tube placement in critically ill children. DESIGN: Single-center retrospective observational study. SETTING: PICU of tertiary children's hospital. PATIENTS: Children under the age of 16 who underwent postpyloric feeding tube placement in our PICU between September 2017 and August 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 115 patients were included in this study: 30 patients underwent ultrasound-guided postpyloric feeding tube placement and 85 patients underwent blind postpyloric feeding tube placement; the insertion attempts were 32 and 93, respectively. There were no significant differences in patient demographics between the ultrasound-guided group and the blind group. The first-pass success rate of the ultrasound-guided group was higher than that of the blind group (94% [30/32] vs 57% [53/93]; p < 0.001). The median insertion time in the ultrasound-guided group with successful postpyloric feeding tube insertion was 18 minutes (interquartile range, 15-25; range, 8-45; n = 21). There were no complications or adverse events during the placement. CONCLUSIONS: In this single-center study, ultrasound-guided postpyloric feeding tube placement was feasible and a significantly high first-pass success rate was observed for critically ill children. Additional investigation with a larger pool of operators and randomized controlled patient assignment is required.

Extracorporeal Life Support as a Treatment of Supraventricular Tachycardia in a Newborn.

ABSTRACT: Supraventricular tachycardia (SVT) is the most common symptomatic tachyarrhythmia in children and requires medical treatment. Thus far, there have been few reports of the use of extracorporeal life support (ECLS) to provide cardiac support in children with low cardiac output resulting from arrhythmia. We present a case of a newborn in whom ECLS was used to provide support for cardiogenic shock secondary to intractable SVT. A 25-day-old girl presented with a 5-hour history of increasing pallor and listlessness. A clinical examination at presentation revealed retractions and peripheral coldness. An electrocardiogram showed a narrow-QRS tachycardia with a rate of 290 beats per minute. Adenosine triphosphate (maximum, 0.2 mg/kg) and synchronous direct current shock (maximum, 25 J) were ineffective. Chest x-ray showed a cardiac dilatation, and echocardiography showed a structurally normal heart with very poor function. The cardiogenic shock caused by SVT was refractory to treatment. The low cardiac output state persisted with worsening metabolic acidosis (bicarbonate, 5.8 mEq/L; lactate, 14.3 mmol/L). In view of the intractable tachyarrhythmia and worsening perfusion, blood access catheters were inserted, and ECLS was initiated. After commencing ECLS support, intravenous adenosine triphosphate (1.25 mg/kg) was administrated. The patient then reverted to a sinus rhythm with a rate of 180 beats per minute. There was considerable improvement of the heart function within 2 days of starting ECLS; the patient was weaned from ECLS support, and the blood access catheters were decannulated on day 3. After weaning from ECLS support, cardiac function returned to normal.

Allele frequencies of Bordetella pertussis virulence-associated genes identified from pediatric patients with severe respiratory infections.

Bordetella pertussis (B. pertussis) infection occasionally causes severe respiratory infections in children. Potential association between virulence-associated gene alleles and severe clinical outcomes has been suggested; however, frequencies of these alleles in pediatric patients with severe pertussis have not been clarified. We retrospectively tested stored respiratory samples collected from B. pertussis-positive patients by polymerase chain reaction targeting for major virulence-associated genes; fimbrae (fim) serotype 3 (fim3), pertactin (prn), pertussis toxin A (ptxA), and pertussis toxin promotor (ptxP). Based on the identified sequences, multilocus sequence typing (MLST) was conducted. Association of gene allele frequency and clinical outcomes such as management in pediatric intensive care unit, intubation, and mortality was analyzed. Out of 25 patients with available samples, the most prevalent allele for each virulence-associated gene was fim3A (17/21, 83%), ptxA1 (20/23, 87%), prn2 (13/16, 81%), and ptxP3 (14/17, 82%). In the study, total of 3 MLST types were identified; MLST-1 from 3 patients (19%), MLST-2 from 10 patients (63%), and MLST-4 from 3 patients (19%). Detection rate of the major MLST type; MLST-2 was significantly higher for patients who required intubation compared to those who did not (6/6, 100% vs 4/10, 40%; p = 0.034). In conclusion, MLST-2 was the most common MLST type in B. pertussis isolated from Japanese children with severe pertussis. Further studies investigating its causal association with disease severity is warranted.

Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib-sensitive and -resistant multiple myeloma cells.

p97/VCP is an endoplasmic reticulum (ER)-associated protein that belongs to the AAA (ATPases associated with diverse cellular activities) ATPase family. It has a variety of cellular functions including ER-associated protein degradation, autophagy, and aggresome formation. Recent studies have shown emerging roles of p97/VCP and its potential as a therapeutic target in several cancer subtypes including multiple myeloma (MM). We conducted a cell-based compound screen to exploit novel small compounds that have cytotoxic activity in myeloma cells. Among approximately 2000 compounds, OSSL_325096 showed relatively strong antiproliferative activity in MM cell lines (IC50 , 100-500 nmol/L). OSSL_325096 induced apoptosis in myeloma cell lines, including a bortezomib-resistant cell line and primary myeloma cells purified from patients. Accumulation of poly-ubiquitinated proteins, PERK, CHOP, and IREα, was observed in MM cell lines treated with OSSL_325096, suggesting that it induces ER stress in MM cells. OSSL_325096 has a similar chemical structure to DBeQ, a known p97/VCP inhibitor. Knockdown of the gene encoding p97/VCP induced apoptosis in myeloma cells, accompanied by accumulation of poly-ubiquitinated protein. IC50 of OSSL_325096 to myeloma cell lines were found to be lower (0.1-0.8 µmol/L) than those of DBeQ (2-5 µmol/L). In silico protein-drug-binding simulation suggested possible binding of OSSL_325096 to the ATP binding site in the D2 domain of p97/VCP. In cell-free ATPase assays, OSSL_325096 showed dose-dependent inhibition of p97/VCP ATPase activity. Finally, OSSL_325096 inhibited the growth of subcutaneous myeloma cell tumors in vivo. The present data suggest that OSSL_325096 exerts anti-myeloma activity, at least in part through p97/VCP inhibition.

The Occurrence and Risk Factors of Inappropriately Deep Tip Position of Microcuff Pediatric Endotracheal Tube During PICU Stay: A Retrospective Cohort Pilot Study.

OBJECTIVES: Cuffed endotracheal tubes are being used increasingly for pediatric patients on mechanical ventilation. Appropriate placement of the tube tip for Microcuff (Kimberley-Clark, Roswell, GA) pediatric endotracheal tube is guided by the intubation depth mark on the device. However, inappropriately deep tip position is sometimes observed during PICU stay. The purpose of this study was to assess the occurrence and risk factors of inappropriately deep tip position of Microcuff pediatric endotracheal tube during PICU stay. DESIGN: A retrospective cohort study. SETTING: The PICU at the National Center for Child Health and Development, one of the largest tertiary pediatric hospitals in Japan. PATIENTS: All patients on mechanical ventilation with Microcuff pediatric endotracheal tube admitted between February 1, 2015, and July 31, 2016, were enrolled. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the occurrence of inappropriately deep tip position, defined as a position of the tube tip less than 5 mm above the carina on a chest radiograph. There were 179 cases (157 patients) requiring mechanical ventilation with Microcuff pediatric endotracheal tube during the study period. An inappropriately deep tip position was found in 42 cases (23.5%), including bronchial intubation in 13 cases (7.3%). In multivariate analysis, height in cm (odds ratio, 0.93; p < 0.001), history of abdominal disease or previous abdominal surgery (odds ratio, 4.38; p = 0.004), and oversized endotracheal tube (odds ratio, 2.93; p = 0.042) were found to be independent risk factors. CONCLUSIONS: The occurrence of inappropriately deep tip position of Microcuff pediatric endotracheal tube during PICU stay was 23.5%. The possibility of an inappropriately deep tip position should be considered whenever patients with the above risk factors, a history of abdominal disease or previous abdominal surgery, and small children are treated or when oversized endotracheal tubes are used.

Benefits of Early Mobilization After Pediatric Liver Transplantation.

OBJECTIVE: To evaluate the impact of early mobilization after pediatric liver transplantation in the PICU. DESIGN: A 70-month retrospective before-after study. SETTING: Medical and surgical PICU with 20 beds at a tertiary children's hospital. PATIENTS: Seventy-five patients 2-18 years old who underwent liver transplantation and could walk before surgery. INTERVENTION: We meticulously planned and implemented an early mobilization intervention, a multifaceted framework for early mobilization practice in the PICU focusing on a multidisciplinary team approach. MEASUREMENTS AND MAIN RESULTS: There was a significant increase in the proportion of patients who received physical therapy in the PICU (66% vs 100%; p < 0.001), especially within the first 48 hours after transplantation (9% vs 78%; p < 0.001). Furthermore, the time spent for physical therapy per eligible patient and per eligible PICU day increased (8.1 min [interquartile range, 0-10.6 min] vs 17.4 min [13.2-26.6 min]; p < 0.001). Compared with patients in the pre-early mobilization period, patients in the post-early mobilization period were able to walk again for more than 50 yards without a rolling walker earlier (28 [16-66] vs 23 [19-31] postoperative days; p = 0.015 by the Gray test), and the length of hospital stay of the post-early mobilization group was shorter than that of the pre-early mobilization group (55 [37-99] vs 40 [31-54] postoperative days; p = 0.012). CONCLUSIONS: Through implementation of early mobilization for pediatric patients who underwent liver transplantation, the duration from liver transplantation to regaining the ability to walk again without a rolling walker became shorter. Early mobilization intervention was beneficial for pediatric patients who underwent liver transplantation and could walk before surgery.

MUC1/KL-6 expression confers an aggressive phenotype upon myeloma cells.

The sialic glycoprotein, MUC1, is known to be involved in the pathogenesis of various types of cancers. KL-6 is one of the surface antigens of MUC1 and also a marker of interstitial pneumonitis. A fraction of patients with myeloma (3.9%) have elevated serum KL-6 levels without any evidence of interstitial pneumonitis and their myeloma cells have high MUC1 expression. We established a myeloma cell line designated EMM1 from a patient with multiple myeloma accompanied with elevated serum KL-6. EMM1 cells expressed high levels of MUC1 compared with other myeloma cell lines. Knockdown of MUC1 in EMM1 cells induced cell cycle arrest during S phase and apoptosis, suggesting that the MUC1 expression is involved in accelerated growth of EMM1 cells. RNA-seq analysis suggests that MUC1 expression activates k-ras and TNFα-induced NFκB pathways in EMM1 cells. We injected EMM1 cells subcutaneously into Rag2-/-Jak3-/- Balb/c mice to establish a mouse xenograft model. These mice had aggressive tumor growth that was accompanied by high serum KL-6 levels. In addition, MUC1 knockdown in EMM1 cells led to inhibited tumor growth. These findings demonstrate that MUC1 serves as a potential target for developing drugs for treatment of patients with KL-6+ myeloma, and EMM1 cells and EMM1-engrafted mice are useful tools for the development of such novel agents.

A xenograft model reveals that PU.1 functions as a tumor suppressor for multiple myeloma in vivo.

We previously demonstrated that PU.1 expression is down-regulated in the majority of myeloma cell lines and primary myeloma cells from patients. We introduced the tet-off system into the human myeloma cell lines U266 and KMS12PE that conditionally express PU.1 and demonstrated that PU.1 induces cell cycle arrest and apoptosis in myeloma cells in vitro. Here, we established a mouse xenograft model of myeloma using these cell lines to analyze the effects of PU.1 on the phenotype of myeloma cells in vivo. When doxycycline was added to the drinking water of mice engrafted with these myeloma cells, all mice had continuous growth of subcutaneous tumors and could not survived more than 65 days. In contrast, mice that were not exposed to doxycycline did not develop subcutaneous tumors and survived for at least 100 days. We next generated mice engrafted with subcutaneous tumors 5-10 mm in diameter that were induced by exposure to doxycycline. Half of the mice stopped taking doxycycline-containing water, whereas the other half kept taking the water. Although the tumors in the mice taking doxycycline continued to grow, tumor growth in the mice not taking doxycycline was significantly suppressed. The myeloma cells in the tumors of the mice not taking doxycycline expressed PU.1 and TRAIL and many of such cells were apoptotic. Moreover, the expression of a cell proliferation marker Ki67 was significantly decreased in tumors from the mice not taking doxycycline, compared with that of tumors from the mice continuously taking doxycycline. The present data strongly suggest that PU.1 functions as a tumor suppressor of myeloma cells in vivo.

Successful venoarterial extracorporeal membrane oxygenation for postoperative septic shock in a child with liver transplantation: A case report.

Refractory septic shock after LT is a life-threatening complication. VA ECMO is used to treat refractory cardiorespiratory failure. We present herein the case of a 5-year-old girl with post-Kasai biliary atresia, who underwent a living donor LT and suffered refractory septic shock. VA ECMO was indicated due to progressive cardiac deterioration. After full recovery of her EF, she has been steadily improving and has shown good liver function and no neurological sequelae. This is the first report of successful VA ECMO in a post- LT patient with refractory septic shock.

Immunomodulatory drugs act as inhibitors of DNA methyltransferases and induce PU.1 up-regulation in myeloma cells.

Immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide are efficacious in the treatment of multiple myeloma and significantly prolong their survival. However, the mechanisms of such effects of IMiDs have not been fully elucidated. Recently, cereblon has been identified as a target binding protein of thalidomide. Lenalidomide-resistant myeloma cell lines often lose the expression of cereblon, suggesting that IMiDs act as an anti-myeloma agent through interacting with cereblon. Cereblon binds to damaged DNA-binding protein and functions as a ubiquitin ligase, inducing degradation of IKZF1 and IKZF3 that are essential transcription factors for B and T cell development. Degradation of both IKZF1 and IKZF3 reportedly suppresses myeloma cell growth. Here, we found that IMiDs act as inhibitors of DNA methyltransferases (DMNTs). We previously reported that PU.1, which is an ETS family transcription factor and essential for myeloid and lymphoid development, functions as a tumor suppressor in myeloma cells. PU.1 induces growth arrest and apoptosis of myeloma cell lines. In this study, we found that low-dose lenalidomide and pomalidomide up-regulate PU.1 expression through inducing demethylation of the PU.1 promoter. In addition, IMiDs inhibited DNMT1, DNMT3a, and DNMT3b activities in vitro. Furthermore, lenalidomide and pomalidomide decreased the methylation status of the whole genome in myeloma cells. Collectively, IMiDs exert demethylation activity through inhibiting DNMT1, 3a, and 3b, and up-regulating PU.1 expression, which may be one of the mechanisms of the anti-myeloma activity of IMiDs.

Complete remission achieved in a multiple myeloma patient with elevated serum KL-6 level by a combination regimen with bortezomib, cyclophosphamide, and dexamethasone.

A 79-year-old woman suffering from double vision after a 4-year history of MGUS was referred to our hospital. MRI revealed that she had three intracranial plasmacytoma masses and one spinal plasmacytoma mass. Bone marrow aspirates showed 52.4% plasma cell infiltration and immunoelectrophoresis identified serum IgG-M protein, leading to a diagnosis of IgG-type multiple myeloma. IgG was elevated to 3,355 mg/dl and urine type Bence-Jones protein was positive. KL-6, a membrane-bound glycoprotein encoded by Mucin 1 and a marker of interstitial pneumonia, was also elevated to 1,409 mg/dl, but computed tomography of the lungs revealed no obvious pulmonary lesions. Previously reported studies showing that myeloma patients with elevated KL-6 might have a poor prognosis prompted us to treat this patient with a three-drug (bortezomib, cyclophosphamide, and dexamethasone: VCD) combination regimen. When 6 cycles of the regimen had been completed, no M-protein was detectable in her serum. Furthermore, κ free light chain had significantly decreased from 12,700 to 24.8 mg/l. In addition, (18)F-FDG PET/CT revealed reduced mass sizes and no (18)F-FDG uptakes by plasmacytomas. Thus, she was defined as having achieved a stringent complete remission (sCR). We therefore concluded that the VCD combination regimen was highly effective in this multiple myeloma patient with KL-6 elevation.