Histopathologically TMA-like distribution of multiple organ thromboses following the initial dose of the BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech): an autopsy case report.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has spread worldwide. Vaccination is now recommended as one of the effective countermeasures to control the pandemic or prevent the worsening of symptoms. However, its adverse effects have been attracting attention. Here, we report an autopsy case of multiple thromboses after receiving the first dose of the BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech) in an elderly woman. CASE PRESENTATION: A 72-year-old woman with a history of diffuse large B-cell lymphoma in the stomach and hyperthyroidism received the first dose of the BNT162b2 mRNA vaccine and died 2 days later. The autopsy revealed multiple microthrombi in the heart, brain, liver, kidneys, and adrenal glands. The thrombi were CD61 and CD42b positive and were located in the blood vessels primarily in the pericardial aspect of the myocardium and subcapsular region of the adrenal glands; their diameters were approximately 5-40 µm. Macroscopically, a characteristic myocardial haemorrhage was observed, and the histopathology of the characteristic thrombus distribution, which differed from that of haemolytic uraemic syndrome and disseminated intravascular coagulation, suggested that the underlying pathophysiology may have been similar to that of thrombotic microangiopathy (TMA). CONCLUSION: This is the first report on a post-mortem case of multiple thromboses after the BNT162b2 mRNA vaccine. The component thrombus and characteristic distribution of the thrombi were similar to those of TMA, which differs completely from haemolytic uraemic syndrome or disseminated intravascular coagulation, after vaccination. Although rare, it is important to consider that fatal adverse reactions may occur after vaccination and that it is vital to conduct careful follow-up.

Two autopsy cases of rupture of the aorta by fistula formation after thoracic endovascular aortic repair and open stent-grafting on aortic arch aneurysm.

The mortality rate of aortic aneurysm/dissection is low in Japan. Two surgical procedures, the thoracic endovascular aortic repair (TEVAR) and the open stent-grafting have contributed much in survival of such aneurysmal patients. We encountered with two autopsy cases of death by aortic rupture with fistula formation after these procedures. Case 1 is an 85-year-old male who had the history of TEVAR for thoracic aorta aneurysm one and a half year before his death. His endovascular stent-graft was composed of a steel endoskeleton consisting of six Z-shape elements while at autopsy, one of the elements locating at the distal part was found inserted deep into the wall of descending aorta, causing aorto-esophageal fistula. Case 2 is an 88-year-old male who had the history of open stent-grafting for aortic aneurysm eight years ago. At autopsy, the stent-graft was found detached from aorta at its lesser curvature, causing gap formation between the aorta and the stent. Six Z-shaped stent elements, the parts of stent-graft, were found separated from descending aorta and located in the aneurism. Furthermore, three of the separated elements were found inserted deep in the aortic wall, causing aorto-pulmonary fistula. Since aorto-esophageal fistula formation after surgery for aortic aneurysm is very rare in TEVAR and there are no reported cases of death by aorto-pulmonary fistula in the open stent-grafting, these cases are reported here.

Fatal Intracranial Aneurysms and Dissections Causing Subarachnoid Hemorrhage: An Epidemiological and Pathological Analysis of 607 Legal Autopsy Cases.

BACKGROUND: There are no detailed reports, in terms of epidemiology and pathology, on intracranial aneurysms and on dissections that were found in unexpected fatal subarachnoid hemorrhage (SAH) cases. In this report we analyzed, based on large-sized medicolegal autopsy cases, the detailed epidemiology and pathological aspects of both lesions. METHODS: We analyzed 607 autopsy cases of unexpected fatal SAHs including 496 aneurysms and 111 dissections. RESULTS: The following results were obtained: (1) Patients who died of dissections were younger than those who died of aneurysms; (2) symptom prevalence rates of aneurysms were 31.9%, appearing to be lower than those in previous studies; (3) a significantly higher prevalence of clinical symptoms was found in patients with dissections (60.5%) than patients with aneurysms; (4) hypertensive cardiomegaly was indicated in more than 80%, while no obvious difference in incidence in hypertensive cardiomegaly was noted between aneurysms and dissections; (5) aneurysms were found to occur much more frequently in the anterior communicating artery (31.9%) and vertebral arteries (7.5%), while dissections were found much more commonly in vertebral arteries (93.7%); and (6) the size of aneurysms was much smaller in general than that previously regarded as a risk factor of rupturing. CONCLUSIONS: These data might help in the prompt intervention in SAH and also in the prevention of lethal SAH in clinical settings.

Development of a teicoplanin loading regimen that rapidly achieves target serum concentrations in critically ill patients with severe infections.

We performed high-dose loading (12 mg/kg every 12 h for 48 h; 4 doses total) of teicoplanin (TEIC) in patients with severe methicillin-resistant Staphylococcus aureus (MRSA) infections, with the goal of achieving target serum concentration (TEICc) ≥ 15 mg/l within 48 h of starting administration. The safety and effectiveness of the fixed, early-stage administration method were evaluated across a range of kidney dysfunction severity levels. TEIC high-dose loading was administered to 106 patients with MRSA infection from February 2010 to February 2013. After high-dose loading, maintenance doses based on therapeutic drug monitoring (TDM) of TEICc were administered via 30-min intravenous drips, every 24 h. Subjects were divided into 4 groups based on kidney function and renal replacement therapy (RRT) status for safety and effectiveness evaluation: group 1 (G1) did not undergo RRT and exhibited creatinine clearance (Ccr; ml/min/m(2)) >50, group 2 (G2) exhibited Ccr ≤ 50, group 3 (G3) underwent continuous RRT (CRRT), and group 4 (G4) underwent intermittent RRT (IRRT). TEICc was measured after 24, 48, 72, and 144 h, immediately before TEIC administration. Target TEICc was reached in all groups, and bacteriological effectiveness and utility were high in G1, G2, and G3. The maximum TEICc (≥ 28.0 mg/l) and serum albumin (≤ 1.84 g/dl) were associated with organ toxicity. Fixed high-dose loading of TEIC achieved the target therapeutic range (≥ 15 mg/l) within 48 h of the start of administration regardless of kidney dysfunction, and exhibited sufficient utility.

Metabolic autopsy with next generation sequencing in sudden unexpected death in infancy: Postmortem diagnosis of fatty acid oxidation disorders.

The recent introduction of metabolic autopsy in the field of forensic science has made it possible to detect hidden inherited metabolic diseases. Since the next generation sequencing (NGS) has recently become available for use in postmortem examinations, we used NGS to perform metabolic autopsy in 15 sudden unexpected death in infancy cases. Diagnostic results revealed a case of carnitine palmitoyltransferase II deficiency and some cases of fatty acid oxidation-related gene variants. Metabolic autopsy performed with NGS is a useful method, especially when postmortem biochemical testing is not available.

Rupture of abdominal aortic aneurysm associated with long-term steroid therapy--a case report.

We report an autopsy case of bronchial asthma patient with a specific abdominal aortic aneurysm. The aneurysm did not show arteriosclerosis, and a specific saccular morphology was noted above the bifurcation. Histologically, necrosis of the media resembling acute aortic dissociation was observed. However, angiitis was ruled out. In addition, the aneurysm showed a cicatrized, old intimal crack in addition to the rupture site, suggesting repeated failures. The long-term steroid therapy-related fragility of the arterial wall may have been involved in the etiology of the aneurysm.

An autopsy case of bilateral adrenal pheochromocytoma-associated cerebral hemorrhage.

The autopsy findings of a 30-year-old woman who died of cerebral hemorrhage induced by bilateral adrenal pheochromocytoma are presented. The cerebral hemorrhage was shown on the left cerebral hemisphere widely. Her both adrenal glands were severe swelling, and their parenchyma was occupied by a dark red-brown tumorous positive for chromogranin A. The serum catecholamine and their metabolite, vanillylmandelic acid (VMA) levels were markedly high. Furthermore, cardiac hypertrophy and sclerosis of the arteries of various organs had progressed, suggesting an influence of persistent endocrinal hypertension. The measurement of serum VMA level was thought to be valuable for a postmortem diagnosis of pheochromocytoma. Bilateral adrenal pheochromocytoma may have excessively secreted catecholamine and subsequently caused secondary hypertension, leading to cerebral hemorrhage.

Autopsy and genetic diagnosis of 21-hydroxylase deficiency with bilateral testicular tumors in a case under no medication for over one year.

The autopsy findings of an adult patient with 21-hydroxylase deficiency are presented. Genetic analysis of the 21-hydroxylase gene (CYP21A2) was performed for accurate diagnosis of congenital adrenal hyperplasia (CAH), and bilateral testicular tumors were characterized. We report a 29-year-old Japanese man who was diagnosed with CAH (21-hydroxylase deficiency) in infancy and had continued steroid therapy until the age of 28. However, for more than one year, he had not been treated for CAH and was found dead. In the medico-legal autopsy findings, both adrenal glands were enlarged, and hypertrophy of adrenal cortices and bilateral testicular tumors positive for melan-A were observed. Genomic DNA was prepared from cervical lymph nodes collected during autopsy, and CYP21A2 was PCR amplified and sequenced directly using newly designed primers. From the morphological findings, the bilateral testicular tumors were considered to be adrenogenital syndrome (TTAGS). Through the whole sequence of CYP21A2, the intron 2 splice mutation (656)A to (656)G was found. TTAGS were thought to be adrenal rests enlarged by ACTH stimulus. From the autopsy findings and the result of genetic analysis, he was diagnosed with the salt-wasting form of 21-hydroxylase deficiency and his cause of death was presumed to be heart failure based on abnormal electrolytes.

An autopsy case in which self-bloodletting via a cervical blood access led to a fatal outcome.

A 48-year-old woman was found dead on a chair in her living room. She had received dialysis every day because of chronic renal failure for the past 15 years. On a table beside her, there was a mirror and 10-mL syringe on a napkin. A stopper was out of place in a portion of a three-way blood access tube established in the right cervical region, and blood coagulation was noted in the lumen. There was a bloodstained measuring cup on the floor. Autopsy findings included a large number of shunt traces in the bilateral infraclavicular fossae and upper limbs, as well as the cervical blood access terminal reaching the right atrium via the internal jugular vein to superior vena cava. Various organs showed anemia. Neither a fatal lesion nor injury was noted in the main organs. Therefore, this patient may have committed suicide by self-bloodletting via a cervical blood access.

Elevated preoperative serum carcinoembrionic antigen level may be an effective indicator for needing adjuvant chemotherapy after potentially curative resection of stage II colon cancer.

BACKGROUND: To determine the prognostic factors and to rationalize adjuvant therapy, the clinicopathologic data of patients with a stage II colon cancer were analyzed retrospectively. PATIENTS AND METHODS: A total of 392 patients underwent potentially curative resection at the Kurume University Hospital between 1982 and 2005. Postoperative adjuvant chemotherapy using oral fluoropyrimidines was administered in 163 patients, and the other 229 patients underwent surgery alone. Univariate and multivariate analyses for prognostic factors were carried out. RESULTS: Invasive type in gross features, elevated preoperative CEA level, and surgery alone were each an independently significant factor for shorter relapse-free survival, and tumor size <50 mm, invasive type in gross features, elevated preoperative CEA level, and surgery alone were each an independently significant factor for shorter overall survival. The relapse-free survival rate and overall survival rate in the patients who received postoperative adjuvant chemotherapy were significantly higher than those in the patients treated with surgery alone even after stratifying to the preoperative CEA level. CONCLUSION: Patients with an elevated preoperative CEA may be candidates for adjuvant chemotherapy after curative resection in stage II colon cancer. These findings warrant clinical trials to test out the efficacy of adjuvant chemotherapy in stage II colon cancer with an elevated preoperative CEA.

Intraoperative thermal ablation therapy for small colorectal metastases to the liver.

BACKGROUND/AIMS: Thermal ablation (TA) therapies such as microwave coagulation therapy (MCT) and radiofrequency interstitial thermal ablation (RFA) for colorectal metastasis to the liver cannot always achieve a complete tumor cell death, and the multiple insertions of the TA probe may lead to intrahepatic dissemination and/or distant metastasis. METHODOLOGY: The achieved local control rate, any recurrence in the residual liver, and any extrahepatic recurrence has been evaluated in 105 patients who underwent hepatectomy and/or intraoperative TA between 1994 and 2004. RESULTS: A total of 102 unresectable liver metastatic lesions (mean size 21mm) were selectively treated with TA either as initial treatment (32 patients) and/or as re-treatment (18 patients) for recurrence in the residual liver, in combination with hepatectomy. Overall, TA achieved a high local tumor control rate of 95%. Multivariate analysis revealed that initial-TA therapy was not a significant predictive factor of hepatic recurrence or any recurrence. CONCLUSION: TA therapies in combination with hepatectomy may offer increased resectability without increased risk of intrahepatic dissemination or extrahepatic recurrence for certain patients who would otherwise be deemed inoperable, when relatively small tumors are indicated for TA.

Significance of thymidine phosphorylase in metronomic chemotherapy using CPT-11 and doxifluridine for advanced colorectal carcinoma.

BACKGROUND: A phase II study was designed to evaluate the efficacy, safety and predictors for response of metronomic chemotherapy using weekly low-dosage CPT-11 and doxifluridine (5'-DFUR) in 45 patients with metastatic colorectal cancer. PATIENTS AND METHODS: Forty mg/m2 of CPT-11 was administered for 3 consecutive weeks in a 4-week treatment cycle, with 5'-DFUR (800 mg/day) given orally. RESULTS: One or more adverse effects were seen in 42 patients. However, most of these were mild at grade 1 or 2, including only leucopenia in 2, neutropenia in 1, diarrhea in 1 and nausea in 1 as grade 3. The objective response rate was 36% with a median overall survival of 452 days. The response rate in patients with a high expression of thymidine phosphorylase (dThdPase) in tumor cells (47%) was higher (p=0.092) than that (19%) in patients with a low expression. CONCLUSION: The efficacy of metronomic chemotherapy using low-dosage weekly CPT-1 and 5'-DFUR is worthy of further clinical study, especially in patients with a high expression of dThdPase in primary tumor cells.

The expression of vascular endothelial growth factor determines the efficacy of post-operative adjuvant chemotherapy using oral fluoropyrimidines in stage II or III colorectal cancer.

The aim of this study was to determine any correlation between the efficacy of post-operative adjuvant chemotherapy using oral fluoropyrimidines and the vascular endothelial growth factor (VEGF) expression in primary colorectal cancer tissues. The data were reviewed retrospectively on 342 patients with colorectal cancer at stage II or III, who underwent potentially curative resection between 1988 and 1998. Of these, 225 received post-operative administration of oral fluoropyrimidines such as UFT and 5'-DFUR, while the other 117 patients underwent surgery alone. Immunostaining for VEGF was performed using colorectal tumours. Overall, VEGF was positively expressed in primary tumour cells in 48% of patients. The disease-free survival rate and the overall survival rate in the chemotherapy group were higher than those in the surgery-alone group, although not significantly. However, the disease-free survival rate and the overall survival rate were similar between the two groups in patients with a tumour positive for VEGF. Multivariate analysis revealed that the VEGF expression was an independent factor for post-operative recurrence, and the VEGF expression and post-operative adjuvant chemotherapy were an independent factor for overall survival, in addition to the lymph node metastasis and the venous invasion. In conclusion, the efficacy of post-operative adjuvant chemotherapy using oral fluoropyrimidines may not be as great for patients with a tumour positive for VEGF having a greater risk of post-operative recurrence. The results support further investigation on efficacy of molecular targeting therapy for VEGF in combination with oral fluoropyrimidines as post-operative adjuvant therapy in colorectal cancer positive for VEGF.

[Possible influence of psychotropic drugs detected in blood when determining the cause of death in medicolegal autopsy cases in the Tokyo Medical Examiner's Office].

We reviewed the records of 118 medicolegal autopsy cases, in which psychotropic drugs were detected in blood, in the Tokyo Medical Examiner's Office in 1997, to explore how the drug levels were considered in determining the cause of death. Names and doses of the drugs were clear in 70 of 118 cases, and in most cases of the 70 cases, multiple drugs (up to 13 drugs) were prescribed to a person. It was also evident that 75 of the 118 cases had demonstrated psychosis for several months to 38 years prior to death. No information concerning prescriptions or history of psychosis could be obtained in the other cases. The causes of death in these 118 cases were as follows: deaths from specific diseases, 30 cases (25.4%); deaths from extrinsic factors excluding drug intoxication, 22 cases (18.6%); suicide related to drug intoxication, 31 cases (26.3%); deaths from extrinsic factors related to drug intoxication suggestive of suicide, but not confirmed, 19 cases (16.1%); non-suicide, including probable drug intoxication, 13 cases (11.0%); and deaths from malignant syndrome, 3 cases (2.5%). There were cases diagnosed as death from specific diseases based on morphological findings, though drug concentrations in blood were at a toxic or even lethal level. In some cases, drug intoxication was suspected, but drug levels in their blood were at a therapeutic level and there were no identifiable morphological changes directly associated with deaths, resulting in a cause of death other than drug intoxication being indicated. Thus, drug levels detected in the cadaver's blood are not always useful for determining the cause of death. This might be due to poor information on interactions between drugs (including alcohol), pathological changes or genetic variability of drug metabolism and excretion, and so on. Thus, further studies of these aspects are needed in order to make information on drugs detected in the cadaver more useful for determination of cause of death.

Biological features of sporadic colorectal carcinoma with high-frequency microsatellite instability: special reference to tumor proliferation and apoptosis.

BACKGROUND: We evaluated the relationship between biological behavior and microsatellite instability (MSI) status, with or without p53 status, in sporadic colorectal carcinoma. METHODS: MSI was analyzed with regard to biological features such as cellular proliferation and apoptotic cell death, in addition to clinicopathological features, in 87 patients with sporadic colorectal carcinoma. RESULTS: Fourteen (16.1%) of 87 tumors showed instability at two or more of the five loci examined (high-frequency MSI [MSI-H]). Four demonstrated instability at one locus (low-frequency MSI [MSI-L]), and 69 showed no instability (microsatellite-stable [MSS]). The MSI-H tumors tended to be located in the proximal colon and more often were mucinous carcinoma. The MSI-H tumors also tended to be in patients with multiple colorectal carcinomas and to demonstrate, rarely, an infiltrating growth pattern or venous invasion. The incidence of p53 protein overexpression in the MSI-H tumors was significantly lower than that in the MSI-L/MSS tumors (21% vs 54%). There was no significant difference in the proliferating-cell nuclear antigen (PCNA) labeling index (PI) or apoptotic index (AI) between the MSI-H and MSI-L/MSS tumors. The AI in the MSI-H tumors with p53 overexpression was significantly lower than that in the MSI-H tumors without p53 overexpression, and was also significantly lower than that in the MSI-L/MSS tumors with p53 overexpression. In the MSI-H tumors with p53 overexpression, no expression of BAX protein was found, and there was high expression of bcl-2 protein, resulting in a low BAX/bcl-2 ratio. CONCLUSION: In sporadic colorectal carcinoma, an MSI-H tumor with p53 protein overexpression may display aggressive biological features.

Production and characterization of murine monoclonal anti-human DNase II antibodies, and their use for immunoaffinity purification of DNase II from human liver and urine.

Four murine monoclonal anti-human deoxyribonuclease II (DNase II) antibodies were obtained from BALB/c mice immunized with human DNase II purified from human liver. Both single radial enzyme diffusion (SRED) and DNA-cast polyacrylamide gel electrophoresis (DNA-cast PAGE) were very useful for obtaining the DNase II-specific antibodies. All of the antibodies showed specific inhibition of human DNase II enzyme activity and specific immunostaining of the 32-kDa enzyme band, which is one of the three non-identical subunits of human DNase II molecule separated by sodium dodecyl sulfate (SDS)-PAGE followed by blotting on a transfer membrane. A formyl-cellulofine resin conjugated with each antibody specifically adsorbed and efficiently desorbed the active DNase II enzyme. Insertion of the immunoaffinity step in our purification procedure made the purification of human DNase II easier, faster and more effective than the conventional procedure.