Fosfomycin as salvage therapy for persistent methicillin-resistant Staphylococcus aureus bacteremia: A case series and review of the literature.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia can be persistent and refractory; however, the optimal approach for its treatment has not been determined. Although fosfomycin (FOM) has been shown to have synergistic effects with anti-MRSA agents in vitro, clinical experience with FOM combination therapy is limited. Thus, we present cases of persistent MRSA bacteremia that improved with the addition of FOM. In case 1, a 48-year-old man with prosthetic vascular graft infection developed persistent MRSA bacteremia despite vancomycin (VCM) and daptomycin (DAP) administration. On day 46, after the first positive blood culture, we added FOM to DAP. The blood culture became negative on day 53. In case 2, an 85-year-old woman presented with pacemaker-related MRSA bacteremia. She was treated with VCM, followed by DAP and DAP plus rifampicin. However, the bacteremia persisted for 32 days because of difficulties in immediate pacemaker removal. After adding FOM to DAP, the blood culture became negative on day 38. In case 3, a 57-year-old woman developed persistent MRSA bacteremia due to pulmonary valve endocarditis and pulmonary artery thrombosis after total esophagectomy for esophageal cancer. The bacteremia continued for 50 days despite treatment with DAP, followed by VCM, VCM plus minocycline, DAP plus linezolid (LZD), and VCM plus LZD. She was managed conservatively because of surgical complications. After adding FOM to VCM on day 51, the blood culture became negative on day 58. FOM combination therapy may be effective in eliminating bacteria and can serve as salvage therapy for refractory MRSA bacteremia.

Consulting a neurosurgeon upon initial medical assessment reduces the time to the first surgery and potentially contributes to improved prognosis for glioblastoma patients.

BACKGROUND: The neurological status of glioblastoma patients rapidly deteriorates. We recently demonstrated that early diagnosis and surgery within 3 weeks from the initial symptoms are associated with improved survival. While glioblastoma is a semi-urgent disease, the prehospital behaviors and clinical outcomes of glioblastoma patients are poorly understood. We aimed to disclose how prehospital patient behavior influences the clinical outcomes of glioblastoma patients. METHODS: Isocitrate dehydrogenase-wildtype glioblastoma patients treated at our institution between January 2010 and December 2019 were reviewed. Patients were divided into two groups, neurosurgeon and non-neurosurgeon groups, based on the primary doctor whom patients sought for an initial evaluation. Patient demographics and prognoses were examined. RESULTS: Of 170 patients, 109 and 61 were classified into the neurosurgeon and non-neurosurgeon groups, respectively. The median age of neurosurgeon group was significantly younger than the non-neurosurgeon group (61 vs. 69 years old, P = 0.019) and in better performance status (preoperative Karnofsky performance status scores $\ge$80: 72.5 vs. 55.7%, P = 0.027). The neurosurgeon group exhibited a significantly shorter duration from the first hospital visit to the first surgery than the non-neurosurgeon group (18 vs. 29 days, P < 0.0001). Furthermore, the overall survival of the neurosurgeon group was significantly more prolonged than that of the non-neurosurgeon group (22.9 vs. 14.0 months, P = 0.038). CONCLUSION: Seeking an initial evaluation by a neurosurgeon was potentially associated with prolonged survival in glioblastoma patients. A short duration from the first hospital visit to the first surgery is essential in enhancing glioblastoma patient prognosis.

Impact of interstitial lung abnormality on survival after adjuvant durvalumab with chemoradiotherapy for locally advanced non-small cell lung cancer.

INTRODUCTION: Concurrent chemoradiotherapy (CCRT) has been the standard of care for patients with locally advanced non-small cell lung cancer (LA-NSCLC). BACKGROUND AND PURPOSE: The results of the PACIFIC trial established the use of consolidative durvalumab after concurrent chemoradiotherapy (CCRT) as the standard of care for patients with locally advanced non-small cell lung cancer (LA-NSCLC). A subgroup analysis of the PACIFIC trial reported a better progression-free survival (PFS) in Asians. Although real-world data on LA-NSCLC patients who received CCRT plus durvalumab have been reported, there have been few large-scale reports on Asians. In this study, we investigated prognostic factors in the largest real-world data set in Asia of only Japanese LA-NSCLC patients treated with CCRT plus durvalumab. MATERIALS AND METHODS: One hundred and thirteen LA-NSCLC patients who received definitive CCRT and consolidative durvalumab at our institution between May 2018 and April 2021 were analyzed. Overall survival (OS), cause-specific survival (CSS), PFS, distant metastasis-free survival (DMFS), and in-field progression-free survival (IFPFS) were investigated as treatment outcomes using competing risk analyses. RESULTS: During a median follow-up of 24 months (range, 5-47) after the initiation of durvalumab therapy, 31 patients died, of whom 23 died of lung cancer. In the multivariate analysis, the pretreatment factors that correlated with OS were ILA scores, adenocarcinoma, and performance status at the initiation of durvalumab. Furthermore, ILA score and programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 1 % were significantly correlated with CSS, and PD-L1 TPS ≥ 1 % was significantly correlated with PFS and IFPFS. CONCLUSION: Pretreatment ILA, adenocarcinoma, and performance status may have an impact on OS of LA-NSCLC patients receiving CCRT plus durvalumab.

Nelarabine-induced myelopathy in patients undergoing allogeneic hematopoietic cell transplantation: a report of three cases.

Nelarabine is an effective treatment for T-cell acute lymphoblastic leukemia/lymphoma. Myelopathy is a rare but serious adverse event associated with this drug. Three patients who received nelarabine at the National Cancer Center Hospital from December 2014 to March 2021 developed myelopathy 20 days before, 12 days after, and 29 days after allogeneic hematopoietic cell transplantation (allo-HCT), respectively. Magnetic resonance imaging showed that two of the patients had lesions in the dorsal column or medulla oblongata, and one had no abnormalities in the head or spine. Despite treatment with intravenous immunoglobulin and methylprednisolone, all patients became unable to walk. One patient died on day 101 after allo-HCT due to progressive neurotoxicity. The other two patients showed spontaneous improvement in neurological symptoms, but one died of mucormycosis on day 476. Autopsy revealed spongiosis in the posterior funiculus in both patients who died, and also in the medulla oblongata in one patient. In the surviving patient, positron emission tomography on day 84 showed abnormal accumulation, suggesting continued inflammation. These cases demonstrated pathophysiological features of nelarabine-induced myelopathy and indicate that allo-HCT may worsen the condition. It is necessary to elucidate the underlying mechanism and establish diagnostic methods and therapies.

Current Status and Challenges of Support Environments for New Graduate Occupational Therapists in Japanese Hospitals: A Mixed Method Study.

Introduction: The number of occupational therapists in Japan continues to increase, which has led to an urgent need to improve the educational environment for new graduate occupational therapists. This study attempted to identify the current state and challenges of the educational environment for new graduate occupational therapists in Japan. Methods: We employed a mixed method using quantitative and qualitative data from a questionnaire survey of 1055 chief occupational therapists in Japanese hospitals. The questionnaire consisted of (1) basic information about the respondent and their hospital, (2) educational environment for new graduate occupational therapists at the respondent's hospital, (3) time spent on in-hospital lectures and on-the-job training, and (4) challenges in the clinical education of new graduate occupational therapists. Text data was analysed qualitatively using text mining to create cooccurrence networks. Results: A total of 385 responses were obtained with a response rate of 36.5%. All hospitals had recruited new graduate occupational therapists in the last five years, but more than half of them did not have a philosophy and policy on education and had not prepared guidelines for the completion of occupational therapy education. The cooccurring network of issues in the educational environment for new graduate occupational therapists indicates the need to create standard guidelines, train supervisors, and develop a hospital education system. Conclusion: In the future, the needs of the educational environment for newly graduated occupational therapists should be investigated, and standardised educational guidelines should be developed.

Clinical impact of p16 positivity in nasopharyngeal carcinoma.

Purpose: The clinical characteristics and prognosis of HPV-related nasopharyngeal cancer (NPC) remain controversial. The relationship between p16 status and outcome was retrospectively investigated in the NPC patients. Materials and Methods: Between May 2009 and May 2019, 81 NPC patients who received definitive radiation therapy, in a hospital in Japan, were identified and the prognosis was investigated. p16, p53, and Epstein-Barr virus (EBV) status were assessed. Also, circumferential tumor extent in the nasopharyngeal cavity was assessed on a 5-point scale. Results: Nine and 72 patients were p16-positive and p16-negative, respectively. Fewer patients were EBV-encoded RNA in situ hybridization (EBER-ISH)-positive in the p16-positive group than in the p16-negative group (p < .01). Seventy-five patients were nonkeratinizing NPCs, and six patients were keratinizing NPCs. There were two p16-positive patients among the keratinizing NPCs.The mean circumferential tumor extent scores of 16-positive and p16-negative NPCs were 4.2 and 3.2, respectively with a statistically significant difference (p = .02). Two-year progression-free survival (PFS) of p16-positive and p16-negative patients undergoing chemoradiation therapy were 100% and 69%, respectively (p = .13). Conclusion: In this study conducted in Japan, p16-positive NPC patients are minor but not very low, and the proportion of keratinizing NPCs was small. p16-positive NPCs were seen both in keratinizing and nonkeratinizing NPCs. P16-positive NPC had a tendency of better PFS than p16-negative NPC. This better prognosis might be due to the higher radiosensitivity of the p16-positive cell. Additionally, p16-positive NPCs seemed to spread more extensively in circumference along the nasopharyngeal mucosa than p16-negative NPCs.

Early Diagnosis and Surgical Intervention Within 3 Weeks From Symptom Onset Are Associated With Prolonged Survival of Patients With Glioblastoma.

BACKGROUND: Glioblastoma (GBM) is a rapidly growing and most life-threatening malignant brain tumor. The significance of early treatment to the clinical outcomes of patients with GBM is unclear. OBJECTIVE: To determine whether early diagnosis and surgery improve the preoperative and postoperative Karnofsky performance status (KPS) and prognosis of patients with GBM. METHODS: Data of isocitrate dehydrogenase-wildtype patients with GBM treated at our institution between January 2010 and December 2019 were reviewed. Patients were classified into early or late diagnosis groups with a threshold of 14 days from initial symptoms. In addition, patients were divided into early, intermediate, and late surgery groups with thresholds of 21 and 35 days. Representative symptoms and patient prognoses were examined. RESULTS: Of 153 patients, 72 and 81 were classified into the early and late diagnosis groups. The median tumor volume was significantly smaller in the former group. The proportion of patients with preoperative KPS scores 90 was 48.6% and 29.6% in the early and late diagnosis groups ( P = .016). The early, intermediate, and late surgery groups included 43, 24, and 86 patients. The median overall survival was significantly longer in the early surgery group than in the late surgery group (28.4 vs 18.7 months, P = .006). Multivariate analysis demonstrated that significant predictors of shorter survival included extent of tumor resection (partial or biopsy), preoperative and postoperative KPS 60, and O6-methylguanine-DNA-methyltransferase promoter status (unmethylated). CONCLUSION: Early diagnosis within 2 weeks and surgical interventions within 3 weeks from the symptom onset are associated with prolonged patient survival. Early GBM treatment will benefit patients with GBM.

Non-Robustness of Ang's Risk Classification in Human Papillomavirus-Related Oropharyngeal Squamous Cell Carcinoma in Japanese Patients.

BACKGROUND: Validity of the risk classification by Ang for human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) remains to be studied in the patients treated by modalities other than chemoradiotherapy and in Japanese patients. MATERIALS AND METHODS: Between 2010 and 2018, 122 patients with HPV-related OPSCC in stages III and IV by the TNM classification 7th edition (TNM-7) were treated curatively at a single institution in Japan. The median age was 62.7 years. Over 50% of the patients underwent surgery with or without adjuvant therapy. The influence of multiple factors on survival was analyzed. RESULTS: The amount of smoking dichotomized at 10 pack-year, which was used in Ang's risk classification, was not predictive of prognosis, and Ang's risk classification was not significantly influential on prognosis in multivariate analysis. In the patients treated with definitive radiation therapy, Ang's risk classification was not predictive of the prognosis in univariate analysis. The impact of smoking was significant only in the patients undergoing the definitive operation. CONCLUSIONS: Ang's risk classification was not robust in predicting the prognosis of general Japanese HPV-related OPSCC patients. The amount of smoking might have different prognostic influences depending on the therapeutic method.

Atezolizumab-induced Encephalitis in a Patient with Hepatocellular Carcinoma: A Case Report and Literature Review.

We herein report a case of encephalitis in a 42-year-old woman with hepatocellular carcinoma following atezolizumab plus bevacizumab therapy. After two weeks of treatment, she was admitted for a high fever, impaired consciousness, and convulsive seizure refractory to diazepam. Magnetic resonance imaging revealed a hyperintense splenial lesion. A cerebrospinal fluid test excluded malignancy and infection. These findings were highly suggestive of a diagnosis of encephalitis due to atezolizumab, an immune-related adverse event. Steroid pulse therapy improved the fever and seizure. However, her incomplete right-sided paralysis and aphasia persisted. This is the first case report of encephalitis caused by atezolizumab plus bevacizumab therapy for hepatocellular carcinoma.

Case Report: SAPHO Syndrome Mimicking Bone Metastases During Treatment With Pembrolizumab for Non-small Cell Lung Cancer.

A 69-year-old female with recurrent stage IV squamous cell lung carcinoma and metastatic abdominal lymph node but not bone metastases was being treated with pembrolizumab. Four months after starting the recurrent treatment, the tumour reduced in size but she began to complain of back pain and palmar rash. A bone scan showed uptake lesions in the left sternocostal joints and vertebrae, while spine magnetic resonance imaging (MRI) showed multiple lesions in the thoracic vertebrae. Her heterogeneous lesions, such as skin and multiple bone manifestations, were comprehensively diagnosed as SAPHO syndrome by different experts. Furthermore, the SAPHO syndrome was suspected to be an immune-related adverse event induced by pembrolizumab, and pembrolizumab withdrawal and prednisolone treatment were performed. Subsequently, her symptoms improved and the follow-up imaging findings showed that the bone lesions had almost disappeared. This case demonstrates that SAPHO syndrome mimicking bone metastases developed during treatment with pembrolizumab. SAPHO syndrome is rare and bone lesions related to the disease may be misdiagnosed as bone metastases. Therefore, it is important in the future for various physicians to have a better understanding of SAPHO syndrome and to consider the potential relationship between this disease and immunotherapy.

Initial Experience of Intentional Internal High-Dose Policy Volumetric Modulated Arc Therapy of Neck Lymph Node Metastases ≥ 2 cm in Patients With Head and Neck Squamous Cell Carcinoma.

BACKGROUND AND PURPOSE: Most locoregional recurrences after definitive radiotherapy for head and neck squamous cell carcinoma (HNSCC) develop "in-field." Dose escalation while sparing organs at risk can be a good solution for improving local control without increasing adverse effects. This study investigated the safety and effectiveness of volumetric modulated arc therapy (VMAT) using intentionally internal high-dose policy (IIHDP) to treat neck lymph node metastases (NLNM) ≥ 2 cm in HNSCC patients. MATERIALS AND METHODS: We analyzed 71 NLNM from 51 HNSCC patients who had received definitive radiotherapy to treat NLNM ≥ 2 cm using the VMAT technique in our institution between February 2017 and August 2019. Thirty-seven NLNM from 25 patients were treated using IIHDP VMAT (group A), and 34 NLNM from 27 patients were treated with homogeneous-dose distribution policy (HDDP) VMAT (group B). One patient with three NLNM had one lymph node assigned to group A and the other two to group B. Adverse events and local recurrence-free survival (LRFS) was compared between the two groups. RESULTS: In the median follow-up period of 527 days, there were no significant differences between the groups in terms of dermatitis or mucositis ≥ grade 2/3, but LRFS was significantly longer in group A (p = 0.007). In the Cox regression analysis after adjustment for the propensity score, group A also showed an apparently superior LFRS. CONCLUSION: Our initial experience of IIHDP VMAT suggested that IIHDP VMAT to treat HNSCC neck lymph node metastases measuring ≥ 2 cm was feasible and possibly led to better local control than HDDP VMAT.

Usefulness of Simple Original Interstitial Lung Abnormality Scores for Predicting Radiation Pneumonitis Requiring Steroidal Treatment After Definitive Radiation Therapy for Patients With Locally Advanced Non-Small Cell Lung Cancer.

PURPOSE: Adjuvant durvalumab has become a standard treatment after chemoradiation therapy for patients with locally advanced non-small cell lung cancer (LA-NSCLC). Accordingly, predicting radiation pneumonitis (RP) requiring steroidal treatment (steroid-RP) is of utmost importance because steroidal administration is reported to weaken the effectiveness of immunotherapy. However, grade 2 RP was used as an index of RP in previous studies, but it is an ambiguous definition because it includes not only steroid-RP but also a mild cough requiring only a cough medicine. Therefore, in this study, steroid-RP was used for evaluating RP, and the purpose of this study was to investigate predictive factors of steroid-RP, including original simple interstitial lung abnormality scores (ILASs). METHODS AND MATERIALS: A total of 145 patients with LA-NSCLC who received definitive radiation therapy (DRT) in our institution from January 2014 to May 2017 were identified. Original ILASs, performance status, age, respiratory function, Brinkman index, concurrent administration of chemotherapy, and dose-volume histogram metrics of the lung were analyzed to evaluate their association with steroid-RP. Additionally, 3 diagnostic radiologists evaluated the patients' pre-DRT chest computed tomography images and determined the simple ILASs. ILASs were rated as follows: 0: none; 1: abnormality without honeycombing (ground-glass attenuation, fine reticular opacity, and microcysts); and 2: honeycombing. RESULTS: The median follow-up period was 729 days. Thirty-one patients (21.4%) experienced steroid-RP. In the univariate analysis, lung V5/V10/VS5, Brinkman index, and ILASs were significant predictive factors of steroid-RP. Additionally, multivariate analysis including Brinkman index ≥840, lung V5 ≥37%, and an ILAS ≥1 revealed that only an ILAS (P = .001) was an independent predictive factor of steroid-RP. CONCLUSIONS: The original simple ILAS was an easy-to-use tool and a significant predictive factor of steroid-RP in DRT in patients with LA-NSCLC.

Magnetic resonance imaging findings in 11 cases of dedifferentiated endometrial carcinoma of the uterus.

PURPOSE: We evaluated magnetic resonance imaging (MRI) findings of dedifferentiated endometrial carcinoma (DEC), comprising undifferentiated carcinoma and low-grade endometrioid carcinoma. MATERIALS AND METHODS: We recruited 11 patients with pathologically proven DEC treated at our institute. We evaluated primary lesion size, location and signal intensity on MRI, and prognosis. MRI and pathological findings were compared in eight resected patients. RESULTS: Primary tumors ranged from 16 to 206 mm in diameter. DEC was located at the endometrium in 9 of the 11 patients; the remaining two patients showed diffuse involvement of the enlarged myometrium. These two patients with diffuse involvement type died within 4 months. Of the eight patients who underwent resection, seven had macroscopic intratumoral hemorrhage and six showed a high signal on T1-weighted images or low signal on T2-weighted images. Of the eight resected patients, four had tumor necrosis > 25% and tumor size > 5 cm. In these patients, necrosis appeared as nonenhanced areas on contrast-enhanced MRI. CONCLUSION: MRI findings of DEC showed two patterns: mass-forming type and diffuse myometrial type with poor prognosis. Most patients with DEC had intratumoral hemorrhage, and large tumors (> 5 cm) had gross necrosis, which appeared as nonenhanced areas on contrast-enhanced MRI.

Short-term outcomes of induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF) in locally advanced nasopharyngeal carcinoma.

There is an unmet need for improving survival outcomes of locally advanced nasopharyngeal carcinoma, for example, T4/ N3 stage disease. To this end, we administered induction chemotherapy (IC) with TPF (docetaxel, cisplatin, and fluorouracil) because this stage of disease is associated with a high risk of recurrence and is difficult to control with standard treatments, such as chemoradiotherapy (CRT) alone or CRT followed by adjuvant chemotherapy. The aim of this retrospective single-center study was to clarify the short-term outcomes of locally far-advanced nasopharyngeal carcinoma patients treated with IC-TPF, followed by CRT with cisplatin. Data from 11 patients were extracted from our database, indicating that the overall response rate to IC-TPF, clinical complete response rate after CRT, 1-year progression-free survival, and 1-year overall survival were 73%, 91%, 68%, and 89%, respectively. Hematological toxicity was the most common adverse event reported during IC-TPF with 64% of patients suffering grade 3 or 4 neutropenia, 55% grade 3 or 4 leucopenia and 9% febrile neutropenia. Despite the small number of patients, these data are important because there is a limited number of studies investigating IC-TPF followed by CRT in Japanese patients. This pilot study provides some indication of the short-term effectiveness and toxicity of this therapeutic approach, which may be superior to standard treatments. Long-term follow-up is warranted to assess the effectiveness of IC-TPF in terms of clinical outcome and late-phase toxicity.

The use of hyperbaric oxygen to treat actinic rectal fistula after SpaceOAR use and radiotherapy for prostate cancer: a case report.

BACKGROUND: In definitive radiation therapy for prostate cancer, the SpaceOAR® System, a hydrogel spacer, is widely used to decrease the irradiated dose and toxicity of rectum. On the other hand, periprostatic abscesses formation and rectal perforation are known as rare adverse effects of SpaceOAR. Nevertheless, there is a lack of reports clarifying the association between aggravation of abscesses and radiation therapy, and hyperbaric oxygen therapy (HBOT) is effective for a peri-SpaceOAR abscess and rectal perforation. CASE PRESENTATION: We report a case of a 78-year-old high-risk prostate cancer patient. After SpaceOAR insertion into the correct space, he started to receive external beam radiation therapy (EBRT). He developed a fever, perineal pain and frequent urination after the completion of EBRT, and the magnetic resonance imaging (MRI) revealed a peri-SpaceOAR abscess. Scheduled brachytherapy was postponed, administration of antibiotics and opioid via intravenous drip was commenced, and transperineal drainage was performed. After the alleviation of the abscess, additional EBRT instead of brachytherapy was performed with MRI-guided radiation therapy (MRgRT). On the last day of the MRgRT, perineal pain reoccurred, and MRI and colonoscopy detected the rectal perforation. He received an intravenous antibiotics drip and HBOT, and fully recovered from the rectal perforation. CONCLUSIONS: Our report indicates that EBRT can lead to a severe rectum complication by causing inflammation for patients with a peri-SpaceOAR abscess. Furthermore, HBOT was effective for the peri-SpaceOAR abscess and rectal perforation associated with EBRT.

Prognostic impact of immunohistopathologic features in definitive radiation therapy for nasopharyngeal cancer patients.

Our previous study by Murakami N, Mori T, Nakamura S, Yoshimoto S, Honma Y, Ueno T, Kobayashi K, Kashihara T, Takahashi K, Inaba K, Okuma K, Igaki H, Nakayama Y, Itami J. (J Radiat Res. 2019 Jul 30. pii: rrz053. doi: 10.1093/jrr/rrz053. [Epub ahead of print]) showed that strong expression of epithelial cell adhesion molecule (EpCAM) was associated with radiation resistance in head and neck squamous cell cancer patients (SCC). In this study, the prognostic impact of histopathologic features including EpCAM for nasopharyngeal cancer (NPC) patients was investigated. Since 2009, our institution has performed chemoradiation for locally advanced NPC patients with intensity modulated radiation therapy (IMRT). Tri-weekly adjuvant cisplatin (CDDP, 80 mg/m2) was administered concurrently with definitive radiation therapy 70 Gy in 35 fractions. One month after radiation therapy, adjuvant chemotherapy of three cycles of CDDP/5 fluorouracil (5-FU) was administered. Using a pretreatment biopsy specimen, EBV-encoded small RNA in situ hybridization (EBER-ISH), EpCAM, p16 and p53 were assessed by immunohistochemical analysis. Between May 2009 and September 2017, 51 NPC patients received definitive radiation therapy. Five, 13, 17 and 16 patients were staged as I, II, III and IV, respectively. The median follow-up period for alive patients was 31.1 months (12.4-109.7 months). Three-year overall survival (OS), progression-free survival (PFS) and locoregional control (LRC) were 87.1, 57.1 and 85.7%, respectively. EpCAM, p16 and p53 were not associated with PFS, OS nor LRC. Three-year PFS for patients with keratinizing and non-keratinizing SCC were 25 and 60.5%, respectively (P = 0.033, hazard ratio 4.851 (95% confidence interval 1.321-17.814)).Prognosis of NPC patients with keratinizing SCC was worse than non-keratinizing SCC patients, suggesting a biological difference between the two types of tumor.

Postmortem redistribution mechanism of donepezil in the rat.

Population aging is rapidly advancing in numerous parts of the world and, accordingly, the prevalence of Alzheimer's disease (AD) is rising. The safety of donepezil (DPZ), which is used for AD treatment, has been established in clinical trials. However, some studies have indicated that DPZ may be associated with severe cardiac side effects, and excessive doses may induce toxicity-related symptoms or death. Therefore, the measurement of blood DPZ levels is important for the postmortem investigation of related causes of death. However, postmortem drug concentrations in the blood may not always reflect those obtained antemortem because of the postmortem redistribution (PMR) of drugs. Therefore, the aim of this study was to investigate the potential PMR of DPZ using a rat model. The DPZ concentration was measured using a validated HPLC/Q-TOF-MS system in cardiac and peripheral blood, and in the brain, lungs, myocardium, liver, and thigh muscle at different postmortem intervals (0, 1, 3, 6, 12, and 24h). Overall, the DPZ tissue to peripheral blood ratio decreased throughout the postmortem period. Furthermore, the DPZ concentration increased in the peripheral and cardiac blood but decreased in both of the lungs, postmortem. Furthermore, the blood pH was significantly lowered. We used a perfusion approach to examine the rat lung and heart to further investigate the relationship between the pH and DPZ release from the lungs. The outflow concentrations when the inflow pH changed from 7.4 to 5.5 were approximately 2-fold higher than the inflow pH fixed 7.4. These findings suggest that the antemortem accumulated DPZ in the lungs is released into the pulmonary blood owing to postmortem acidification of blood, and subsequently flows into the cardiac blood, leading to the observed increase in concentration. Although we could not determine the underlying mechanism, we confirmed that PMR occurs similarly in the cardiac and peripheral blood.

Donepezil distribution in postmortem cases and potential for redistribution.

Donepezil (DPZ) is an acetylcholine-esterase inhibitor currently used as the frontline drug to treat Alzheimer's disease. The aim of this study was to investigate the possibility of postmortem redistribution (PMR) of DPZ, which could complicate the determination of cause of death in medico-legal cases. Additionally, metabolic enzyme DNA polymorphism, drug-drug interaction and the presence of lesions in metabolic and egestion organs were examined to eliminate the possibility of a high antemortem DPZ concentration. Subsequently, the average DPZ concentration of four sites of peripheral blood (right and left femoral artery and vein) was compared with central blood and liver DPZ concentrations in seven postmortem cases. DPZ concentrations ranged from 0.02 to 0.45µg/mL in the peripheral blood, 0.09-0.4µg/mL in central blood, and from 1.2 to 6.7µg/kg in the liver. In most specimens, the concentrations were higher than the therapeutic range (approximately 0.030-0.075µg/mL). DPZ central blood to peripheral blood (C/P) ratios averaged 1.73±1.02 (±standard deviation) while liver to peripheral blood (L/P) ratios were higher and averaged 17.5±7.25. It is documented that a C/P ratio of less than (or about) 1.0 and an L/P ratio less than 5 are not indicative of PMR, whereas a C/P ratio exceeding 2 and L/P ratio exceeding 20 highlight a propensity for significant PMR. Our data suggest that DPZ exhibits a moderate degree of PMR. Additionally, a lowered pH was found in all blood specimens (<6-6.75 in the peripheral blood and <6-6.66 in the central blood). This postmortem reduction in blood pH may increase the ionic forms of DPZ, resulting in a high blood DPZ concentration.

Age estimation by quantitative features of pubic symphysis using multidetector computed tomography.

Macroscopic assessment of the pubic symphysis is commonly used for age estimation because its surface changes over time. However, postmortem computed tomography (PMCT), a method several forensic medical departments and institutes have begun to adopt, has the potential to simplify the information gathering process from the pelvic bone without requiring soft tissue removal. Some studies have previously evaluated the use of three-dimensional images of the pubic symphysis, but because of variance in the graphics processing among image analysis software packages, certain differences have been observed between these studies. Therefore, in this study, the PMCT findings of 199 subjects of known age and sex were retrospectively reviewed to examine the feasibility of age estimation using planar images of the pubic bones and soft tissue. The coronal and axial sectional images were observed at the center of the symphyseal surface, and the pubic bone length and thickness of the connective tissue of the pubic symphysis were measured at each slice. Our results revealed a significant positive correlation between the length of the pubic bone of the coronal section and age, suggesting that the use of a cutoff value for pubic bone length might be feasible for age estimations. In addition, the thickness of the connective tissue tended to narrow over time. Although the prediction interval range of planar images obtained by PMCT was major and is not usable in practice at this moment, it may still be a useful tool if used in conjunction with other findings obtained by PMCT.