An autopsy case of adult-onset neuronal intranuclear inclusion disease with perivascular preservation in cerebral white matter.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by appearance of eosinophilic hyaline intranuclear inclusions. While the main symptoms of adult-onset NIID are dementia or limb weakness, some patients present with encephalitic episodes and transient neurological symptoms. The pathophysiology of these acute, transient symptoms, however, remains unknown. Here, we describe an autopsy case of adult-onset NIID with progressive dementia and transient hemiparesis. The patient was a 70-year-old man without a relevant family history, and initially presented with progressive dementia. He then exhibited transient left hemiparesis at 75 years of age and died of ureteral cancer at 77 years of age. Neuropathological examination revealed the presence of multiple areas of focal spongiosis in the subcortical white matter and patchy myelin pallor of the white matter, as in previous reports. However, perivascular areas were preserved even in the damaged white matter. In addition, dense glial fibrillary acidic protein (GFAP)-immunoreactive astrocytic processes were observed in these areas. [Correction added on 23 January 2022, after first online publication: the preceding sentence has been corrected to improve readability.] GFAP immunohistochemistry revealed decreased density and morphological abnormalities of astrocytes in the affected white matter. These pathological findings might reflect blood-brain barrier impairment and dysregulation of blood flow, which may be related to the pathophysiology of the acute, transient symptoms observed in NIID.

Cellular cannibalism and consequent thrombocytopenia in a patient with bone marrow metastasis of malignant pleural mesothelioma: A case report.

Cellular cannibalism is a tumor activity where a cell is engulfed by another cell. This process promotes tumor cell survival under unfavorable conditions. The current report describes an extremely rare case of thrombocytopenia resulting from cellular cannibalism in a patient with bone marrow metastasis due to malignant pleural mesothelioma (MPM). A 77-year-old male presented with hemothorax and thrombocytopenia. He was diagnosed with MPM of the sarcomatoid cell type. However, his disease progressed rapidly and he died 11 days after admission. Bone marrow aspiration revealed metastatic MPM cells that had engulfed other blood cells. Accordingly, the observed thrombocytopenia was attributed to cellular cannibalism by metastatic MPM tumor cells. To the best of our knowledge, this is the first reported case of thrombocytopenia due to cellular cannibalism in a patient with this type of malignancy (MPM). The results suggested that although MPM rarely metastasizes to the bone marrow, bone marrow aspiration could be useful in such cases.

The First Autopsy Case of Fatal Acute Cardiac Failure after Administration of Carfilzomib in a Patient with Multiple Myeloma.

Carfilzomib (CFZ) improves progression-free survival for patients with relapsed or refractory multiple myeloma (MM) but has shown higher frequency of cardiovascular adverse events (CVAEs) than other proteasome inhibitors. We report the first autopsy case of acute death from cardiac failure shortly after administration of carfilzomib. A 74-year-old female was diagnosed with IgA MM after a 2-year period of smoldering MM. She was refractory to both bortezomib plus dexamethasone and lenalidomide plus dexamethasone therapies, so she subsequently received CFZ in combination with lenalidomide and dexamethasone. The day after the start of the therapy, she complained of severe dyspnea with a significant decline in left ventricular ejection fraction. Her acute cardiac failure rapidly progressed, and she died on day 7 of the start of CFZ. The autopsy showed invasion of inflammatory cells between the myocardial cells and very little myocardial necrosis. There was no obvious thrombus in the coronary artery of the heart, and no infarction or amyloid deposition was observed in the myocardium. Pathological findings of hypersensitivity myocarditis, a drug-induced cardiomyopathy, appeared to agree with this case except for absence of an eosinophilic infiltration of the myocardium. A CFZ-induced CVAE is generally considered reversible. However, rapidly progressing fatal heart failure like in our case is rare. To characterize CFZ-associated CVAE, further case collection is needed.

Lymphocyte-depleted classical Hodgkin lymphoma accompanied by myelofibrosis.

A 91-year-old male with fever of unknown origin was referred to our department. 18F-FDG PET/CT scan revealed a high FDG uptake in abdominal lymph nodes and multiple bones. The bone marrow biopsy showed fibrosis and atypical megakaryocytes, which were consistent with myelofibrosis. The patient died 28 days after admission and an autopsy was performed. The lymph nodes and bone marrow specimens revealed scattered Reed-Sternberg cells and a dearth of lymphoid cells with fibrosis. A final diagnosis of lymphocyte-depleted classical Hodgkin lymphoma (LDCHL) with bone marrow involvement was made. It is necessary to identify LDCHL during differential diagnosis for bone marrow fibrosis accompanied by lymphadenopathy.

[A Case of Recurrent Colorectal Cancer with Bilateral Ovarian Metastases That Were Reduced with Regorafenib Therapy].

A 63-year-old woman had recurrences of metastatic rectal cancer in the lung, peritoneum, and ovary. Regorafenib was administered at 160mg/day as third-line chemotherapy. The patient developed Grade(Gr)3 hand-foot syndrome(HFS) and Gr 2 rash, but the abdominal distension and pain were relieved by the 1st course. Analgesics could be reduced and regorafenib was administrated at reduced dosage. The patient received keishi-bukuryo-gan(EK-25)and sai-rei-tou(TJ-114) for HFS. At the beginning of therapy, ovarian metastases were not reduced and showed poor contrast enhancement on CT. Serum levels of lactate dehydrogenase(LDH)and tumor markers were increased. During the 4th course of therapy, ovarian metastases tended to shrink and serum levels of LDH and tumor markers were decreased. Ovarian metastases showed a partial response(PR)after the 6th course. Lung metastases showed a progressive disease during the 2nd course, but a PR after the 3rd course, and were not apparent after the 6th course. Reduction of metastases was maintained at 16 months after the start of therapy, and HFS was assessed at Gr 2 or lower. Physical, laboratory, and imaging findings should be carefully evaluated prior to long-term administration of regorafenib.

Rectal lymph node metastasis in recurrent ovarian carcinoma: essential role of 18F-FDG PET/CT in treatment planning.

Although uncommon, ovarian cancer cells may spread to the rectal lymph nodes. However, few reports have described how to detect and treat such metastases. We report a case of a 59-year-old woman with mesorectal and pararectal lymph node metastases in recurrent ovarian carcinoma, detected conclusively using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT), and treated by low anterior resection with total mesorectal excision aiming for macroscopic complete resection. The treatment goals for the patient were gradually changed from curative to palliative chemotherapy; she survived for 45 months without rectal obstruction after secondary debulking surgery, and was followed up until autopsy. Thus, 18F-FDG PET/CT may be valuable for detecting rectal lymph node metastasis and can play an essential role in planning treatment for recurrent ovarian carcinoma.

[Asymptomatic longterm survival in a patient with sigmoid colon lymph node metastasis with cancerous ascites of unknown origin].

A 63-year-old man bearing a palpable tumor had a lymph node metastasis adjacent to the sigmoid colon that was detected by computed tomography and positron emission tomography. The sigmoid colon and enlarged lymph nodes were surgically resected, and cancerous ascites were present. Pathologically, the tumor in the lymph node was a poorly-differentiated adenocarcinoma that was positive for CA19-9 as well as CK7(-/+), CK20(+/-), VEGF(+), p 53(+)and MIB-1 (>10%). We treated this case as a pancreatic or bile duct carcinoma due to the patient's markedly elevated serum levels of CA19-9 and SPan-1. However, we could not make a conclusive diagnosis. Gemcitabine-based chemotherapy was administered, and the patient had no signs of recurrence for 24 months after the operation. Then, a recurrence was identified by imaging studies, and the chemotherapy was changed to paclitaxel and carboplatin. The patient had stable disease until tumor regrowth was identified 38 months after the operation, chemotherapy was then stopped. However, at 48 months after the operation, the patient remains well and has no symptoms. Our case suggests that surgery and the appropriate choice of anticancer drugs may contribute to the long-term survival of patients with cancer of an unknown primary origin.

[A case with multiple liver metastases from rectal cancer responding completely to FOLFOX for a long duration without exacerbation of peripheral neuropathy].

A 61-year-old man had undergone five courses of modified FOLFOX6(mFOLFOX6)chemotherapy with calcium-magnesium(Ca/Mg)infusion for a rectal cancer with multiple liver metastases from October 2008. After this treatment, the primary rectal tumor and metastatic tumors were considered as a partial response(PR), and lower anterior resection was carried out in February 2009. After the operation, mFOLFOX6 chemotherapy with bevacizumab was started in March 2009. After 15 courses of chemotherapy, the patient received 7. 5 g of gosha-jinki-gan(TJ-107)daily from August 2009, and the drug compliance was 69%. From the 18th course of chemotherapy in October 2009, glutathione(GSH)was given at a dose of 200 mg before each oxaliplatin administration. From the 35th course of chemotherapy in November 2010, the patient received 1. 5 g of powdered processed aconite root(TJ-3027)daily. TJ-3027 administration was escalated to 4. 5 g daily, and drug compliance was 73%. Grade 4 neutropenia was observed in December 2010, and we reduced oxaliplatin to 65 mg/m(2) from the 37th course. Fifty chemotherapy courses were administered until October 2011. The patient received a total 3, 970 mg/m(2) of oxaliplatin, however, the neurotoxicity level of the patient remained at grade 2. Ca/Mg infusion and TJ-107 administration have been reported not to reduce the activity of FOLFOX individually, and severe side effects are rare. So one must consider the combination treatment of Ca/Mg and TJ-107 for prevention of oxaliplatin-related neurotoxicity.

Utility of immunohistochemical analysis of KAI1, epithelial-specific antigen, and epithelial-related antigen for distinction of chromophobe renal cell carcinoma, an eosinophilic variant from renal oncocytoma.

Distinction of renal oncocytoma (RO) from chromophobe renal cell carcinoma (ChRCC) is important because their clinical behavior is different. As part of a search for the best available immunohistochemical markers to distinguish ChRCC from RO, we investigated the immunohistochemical profiles of these tumors. We selected 30 renal tumors consisting of ChRCC, typical variant (n = 14), ChRCC, eosinophilic variant (n = 6), and RO (n = 10). Their expression of cytokeratin (CK) 7, KAI1, epithelial-specific antigen (ESA), epithelial-related antigen (ERA), Claudin- 7, and Claudin-8 was studied using an autostainer. Immunoreactivity was assessed based on a combined score of the extent and intensity of staining. Compared to RO, a significantly higher percentage of the total ChRCCs stained positive for CK7 (85% vs. 10%, respectively), KAI1 (90% vs. 10%), ESA (95% vs. 10%), ERA (95% vs. 10%), and Claudin-7 (95% vs. 20%) (P < 0.001). Additionally, there was a significant difference between the percentage of ChRCC eosinophilic variant (ChRCC-E) and RO that stained positive for KAI1 (100% vs. 10%, respectively), ESA (83% vs. 10%), and ERA (83% vs. 10%) (P < 0.001). We recommend immunohistochemical analysis of KAI1, ESA, and ERA to distinguish ChRCC-E from RO.

Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts.

Cortical microinfarcts (CMIs) observed in brains of patients with Alzheimer's disease tend to be located close to vessels afflicted with cerebral amyloid angiopathy (CAA). CMIs in Alzheimer's disease are preferentially distributed in the arterial borderzone, an area most vulnerable to hypoperfusion. However, the causal association between CAA and CMIs remains to be elucidated. This study consists of two parts: (1) an observational study using postmortem human brains (n = 31) to determine the association between CAA and CMIs, and (2) an experimental study to determine whether hypoperfusion worsens CAA and induces CMIs in a CAA mouse model. In postmortem human brains, the density of CMIs was 0.113/cm(2) in mild, 0.584/cm(2) in moderate, and 4.370/cm(2) in severe CAA groups with a positive linear correlation (r = 0.6736, p < 0.0001). Multivariate analysis revealed that, among seven variables (age, disease, senile plaques, neurofibrillary tangles, CAA, atherosclerosis and white matter damage), only the severity of CAA was a significant multivariate predictor of CMIs (p = 0.0022). Consistent with the data from human brains, CAA model mice following chronic cerebral hypoperfusion due to bilateral common carotid artery stenosis induced with 0.18-mm diameter microcoils showed accelerated deposition of leptomeningeal amyloid ß (Aß) with a subset of them developing microinfarcts. In contrast, the CAA mice without hypoperfusion exhibited very few leptomeningeal Aß depositions and no microinfarcts by 32 weeks of age. Following 12 weeks of hypoperfusion, cerebral blood flow decreased by 26% in CAA mice and by 15% in wild-type mice, suggesting impaired microvascular function due to perivascular Aß accumulation after hypoperfusion. Our results suggest that cerebral hypoperfusion accelerates CAA, and thus promotes CMIs.

A case report of surgical resections with local and systemic chemotherapy for three recurrences of colon cancer occurring ten years after colectomy.

A 56-year-old Japanese woman who underwent a curative resection of ascending colon cancer at 43 years of age was found to have a tumor in her lower left abdominal cavity by computed tomography at 53 years of age. The tumor in the omentum was resected and identified as an adenocarcinoma compatible with metastasis from the primary ascending colon cancer. Although the patient received adjuvant chemotherapy with tegafur uracil and calcium folinate, liver metastasis was detected 9 months after the first recurrence. A segmentectomy and hepatectomy was performed, and histopathological findings indicated metastasis from the primary colon cancer. A third recurrence was detected in the right abdominal cavity 7 months after the second surgery. The patient received 5 cycles of combination chemotherapy consisting of folinic acid, fluorouracil and irinotecan before the third operation. The metastatic tumor resection together with intraperitoneal chemotherapy was performed, and histopathological findings indicated metastasis from the primary colon cancer. After the third surgery, the patient received adjuvant chemotherapy consisting of 5 cycles of folinic acid, fluorouracil and oxaliplatin. The patient is well with no evidence of recurrence 12 months after the third recurrence. This case suggests that colon cancer can be dormant for over 10 years and that long-term follow-up is required after curative resection. Aggressive local as well as systemic chemotherapy may be required for the management of colon cancer recurrence.

Intravascular large B-cell lymphoma diagnosed by FDG-PET/CT and endometrial biopsy.

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of non-Hodgkin's lymphoma characterized by a proliferation of tumor cells within the lumina of small to medium-sized vessels. Because there are few or no concomitant solid lesions, a diagnosis of IVLBCL usually cannot be established by CT or MR imaging. Herein, we describe a case of IVLBCL involving the uterus, in which (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) was useful for diagnosis. A 47-year-old woman was referred to our hospital because of fever and anemia. Laboratory examination demonstrated anemia and thrombocytopenia. Bone marrow aspiration and biopsy showed hemophagocytosis without involvement of lymphoma cells. Random skin biopsy did not demonstrate lymphoma involvement. FDG-PET/CT imaging showed FDG accumulation in the uterus. MR imaging demonstrated uterine leiomyoma only. Based on these findings, uterine endometrial biopsy was performed and histological diagnosis of IVLBCL involving the uterus was established. She received 6 courses of R-CHOP therapy and high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation. At present, she remains in complete remission after 33 months.

Usefulness of F-18 FDG-PET in a long-term hemodialysis patient with renal cell carcinoma and pheochromocytoma.

A patient who had been on long-term hemodialysis (HD) was diagnosed as having renal cell carcinoma (RCC) and pheochromocytoma. Abdominal computed tomography scanning demonstrated a right renal mass and a right adrenal mass, whereas positron emission tomography (PET) using F-18 fluorodeoxyglucose (FDG) revealed increased accumulation in both the renal and adrenal masses. FDG-PET is useful for detecting RCC in HD patients because FDG is not excreted in the urine, but it is difficult to distinguish pheochromocytoma from an adrenal metastasis by this imaging method.

[A case of hepatic actinomycosis diagnosed by thin needle aspiration biopsy successfully treated with antibiotics].

A 57-year-old man presented with chief complaints of right hypochondrial pain and fever. Laboratory tests revealed severe inflammatory reactions. Abdominal ultrasonography disclosed a mass with non-homogeneous internal echoes suggesting hepatic abscess. Percutaneous liver biopsy revealed a lump of actinomycetes, allowing a diagnosis of hepatic actinomycosis. The abscess disappeared following long-term treatment with penicillin antibiotics. Actinomycosis developing primarily in the liver is very rare. This condition needs to be distinguished from tumorous lesions of the liver, including malignancy. It seems noteworthy that the diagnosis of this condition was possible on the basis of percutaneous liver biopsy.

Conjugated docosahexaenoic acid is a potent inducer of cell cycle arrest and apoptosis and inhibits growth of colo 201 human colon cancer cells.

The effect of conjugated docosahexaenoic acid (CDHA) on the inhibition of colon cancer cell growth was examined in the colo 201 human colon cancer cell line, and the effect was compared with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). CDHA was a more potent tumor cell growth inhibitor than DHA and EPA by colorimetric 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay (IC50 for 72 h: 31.6 microM, 46.8 microM, and 56.6 microM, respectively). CDHA inhibited cell cycle progression, due to accumulation of cells in G1 phase, which involved increased p21Cip1/Waf1 and decreased cyclin D1, cyclin E, and proliferating cell nuclear antigen expression; the p53 and cyclin A levels were unchanged. Induction of apoptosis was confirmed by the appearance of sub-G1 populations, and apoptosis cascade involved upregulation of the apoptosis-enhancing proteins (Bak and Bcl-xS) and downregulation of the apoptosis-suppressing proteins (Bcl-xL and Bcl-2). CDHA modulated cell cycle regulatory proteins and apoptosis-related proteins, similar to the effects of DHA. CDHA at a dietary dose of 1.0% significantly inhibited growth of colo 201 cells transplanted in nude mice.

Conjugated docosahexaenoic acid suppresses KPL-1 human breast cancer cell growth in vitro and in vivo: potential mechanisms of action.

INTRODUCTION: The present study was conducted to examine the effect of conjugated docosahexaenoic acid (CDHA) on cell growth, cell cycle progression, mode of cell death, and expression of cell cycle regulatory and/or apoptosis-related proteins in KPL-1 human breast cancer cell line. This effect of CDHA was compared with that of docosahexaenoic acid (DHA). METHODS: KPL-1 cell growth was assessed by colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay; cell cycle progression and mode of cell death were examined by flow cytometry; and levels of expression of p53, p21Cip1/Waf1, cyclin D1, Bax, and Bcl-2 proteins were examined by Western blotting analysis. In vivo tumor growth was examined by injecting KPL-1 cells subcutaneously into the area of the right thoracic mammary fat pad of female athymic mice fed a CDHA diet. RESULTS: CDHA inhibited KPL-1 cells more effectively than did DHA (50% inhibitory concentration for 72 hours: 97 micromol/l and 270 micromol/l, respectively). With both CDHA and DHA growth inhibition was due to apoptosis, as indicated by the appearance of a sub-G1 fraction. The apoptosis cascade involved downregulation of Bcl-2 protein; Bax expression was unchanged. Cell cycle progression was due to G0/G1 arrest, which involved increased expression of p53 and p21Cip1/Waf1, and decreased expression of cyclin D1. CDHA modulated cell cycle regulatory proteins and apoptosis-related proteins in a manner similar to that of parent DHA. In the athymic mouse system 1.0% dietary CDHA, but not 0.2%, significantly suppressed growth of KPL-1 tumor cells; CDHA tended to decrease regional lymph node metastasis in a dose dependent manner. CONCLUSION: CDHA inhibited growth of KPL-1 human breast cancer cells in vitro more effectively than did DHA. The mechanisms of action involved modulation of apoptosis cascade and cell cycle progression. Dietary CDHA at 1.0% suppressed KPL-1 cell growth in the athymic mouse system.