Reported herein is the case of a 70‐year‐old man with high grade urothelial carcinoma (UC) with rhabdoid features of the renal pelvis. For the most part, the tumor was composed of pleomorphic, ...non‐cohesive round tumor cells with abundant cytoplasm. In situ high‐grade UC composed of cohesive tumor cells was seen only in a small portion. Pleomorphic dyscohesive tumor cells often showed rhabdoid features, containing eosinophilic inclusions. These pleomorphic/rhabdoid tumor cells were immunohistochemically positive for vimentin but negative for cytokeratins, CD45, CD20, CD79a, CD3, CD45RO, CD38, and CD138. Loss of heterozygosity (LOH) analysis demonstrated identical allelic losses as well as additional allelic losses for the dyscohesive and cohesive UC lesion, indicating that these two lesions originated from a single clonal lesion.
Abstract
Context.—Myofibroblasts are considered to play central roles in pancreatic fibrosis. The potent fibrogenic capacities of transforming growth factor βs (TGF-βs) have been emphasized in vitro ...and in animal studies. However, the roles of TGF-βs in human chronic pancreatitis have not been fully clarified.
Objective.—To investigate whether expressions of TGF-βs are related to myofibroblast distribution in chronic, cancer-associated, obstructive pancreatitis (COP).
Design.—Histopathologic studies using hematoxylin-eosin and Elastica-Masson trichrome and immunohistochemical studies using antibodies against α-smooth muscle actin (SMA); CD68; TGF-β1, -β2, and -β3; and TGF-β soluble receptor type II were performed in 19 COP cases and 6 controls. By classifying COP tissues into 3 fibrosis phases by the amount of collagen deposits, immunoreactivities for TGF-βs, histopathologic changes, and myofibroblast distribution were examined for each fibrosis phase.
Results.—Six cases were categorized in the early stage of fibrosis, 8 in the intermediate stage, and 5 in the advanced stage. Immunoreactivities for all 3 isoforms of TGF-β were observed in occasional myofibroblasts. In the early and intermediate stages, TGF-β1–expressing macrophages and neutrophils were distributed in the midst of myofibroblasts. TGF-β2 and TGF-β3 expressions were observed in ductal structures, sometimes even in sites where no or few myofibroblasts were seen. TGF-β soluble receptor type II was immunoreactive for myofibroblasts, endothelium, and ductal structures.
Conclusions.—All 3 isoforms of TGF-βs may contribute to fibrosis in COP. Macrophages and neutrophils may be sources of fibrogenic TGF-β1. Infiltration of these cells appears to play an important role in the progression of COP fibrosis.
A 30-year-old Japanese woman with lymphangioleiomyomatosis (LAM) developed a left chylothorax and chylous ascites. A pleuro-peritoneal communication was confirmed by a scintigram with 99mTc-labeled ...macroaggregated-albumin injected into the peritoneal cavity. Video-assisted thoracic surgery revealed a protruding papillary lesion on the left diaphragm. Chyle was oozing into the pleural cavity through this lesion. Histopathological analyses demonstrated that the protrusion was a diaphragmatic LAM lesion and that LAM-associated lymphangiogenesis enabled communication between the pleural and peritoneal cavities through lymphatic vessels. This case demonstrated a new mechanism for chylous pleural effusion in LAM and illustrates the significance of LAM-associated lymphangiogenesis.
A 37-year-old woman presented with a cough and discomfort in the chest. Computed tomography revealed the right pleural effusion and a number of cysts in the lungs. Thoracentesis revealed LAM cell ...clusters (LCC) in chylous pleural effusion, confirmed by immunocytochemical examinations showing that the cells at the center of cluster were LAM cells positive for α-smooth muscle actin and HMB45 and the outer layer was lymphatic endothelium cells. When LCC were cultured in vitro, the loss of heterozygosity of TSC2 markers was detected. This case illustrates that LAM can be diagnosed by the identification of LCC without an invasive biopsy if complicated with chylous effusion.
Pancreatic cancer has the poorest survival rate among all cancer types. Therefore, it is essential to develop an effective treatment strategy for this cancer.
We performed carbon ion radiotherapy ...(CIRT) in human pancreatic cancer cell lines and analyzed their survival, apoptosis, necrosis, and autophagy. To investigate the role of CIRT-induced autophagy, autophagy inhibitors were added to cells prior to CIRT. To evaluate tumor formation, we inoculated CIRT-treated murine pancreatic cancer cells on the flank of syngeneic mice and measured tumor weight. We immunohistochemically measured autophagy levels in surgical sections from patients with pancreatic cancer who received neoadjuvant chemotherapy (NAC) plus CIRT or NAC alone.
CIRT reduced the survival fraction of pancreatic cancer cells and induced apoptotic and necrotic alterations, along with autophagy. Preincubation with an autophagy inhibitor accelerated cell death. Mice inoculated with control pancreatic cancer cells developed tumors, while those inoculated with CIRT/autophagy inhibitor-treated cells showed significant evasion. Surgical specimens of NAC-treated patients expressed autophagy comparable to control patients, while those in the NAC plus CIRT group expressed little autophagy and nuclear staining.
CIRT effectively killed the pancreatic cancer cells by inhibiting their autophagy-inducing abilities.
This is the first case report of gastric plasmacytoma associated with “
Candidatus Helicobacter heilmannii
” (‘
H. heilmannii
’) infection. The patient was a 40-year-old woman with epigastric ...discomfort. Upper gastrointestinal endoscopy demonstrated a white granular lesion on the wall of the gastric body. Histological studies showed numerous eosinophilic globules expanding the lamina propria mucosae. Immunohistochemically, the cells with these globules stained positive for CD138, CD79a, immunoglobulin (Ig) M, and kappa light chain, but negative for CD20, IgG, IgA, and lambda light chain. A diagnosis of plasmacytoma was made. Although a
Helicobacter pylori
infection was not detected, the patient received
H. pylori
eradication treatment. Two months after
H. pylori
eradication treatment, an upper gastrointestinal endoscopy showed a reduction of the white granular lesion. Eighteen months after eradication treatment, endoscopy, endoscopic ultrasonography and histological studies revealed complete remission of the lesion. No relapse has been documented 30 months after the initial diagnosis of plasmacytoma. Retrospectively, analysis of biopsy specimens removed before eradication treatment demonstrated that this patient had ‘
H. heilmannii
’ infection. Therefore,
H. pylori
eradication therapy should be considered as a potential first-line therapy for early-stage gastric plasmacytoma with or without
H. pylori
infection.
Targeted therapies based on the molecular and histological features of cancer types are becoming standard practice. The most effective regimen in lung cancers is different between squamous cell ...carcinoma (SCC) and adenocarcinoma (AD). Therefore a precise diagnosis is crucial, but this has been difficult, particularly for poorly differentiated SCC (PDSCC) and AD without a lepidic growth component (non-lepidic AD). Biomarkers enabling a precise diagnosis are therefore urgently needed.
Cap Analysis of Gene Expression (CAGE) is a method used to quantify promoter activities across the whole genome by determining the 5' ends of capped RNA molecules with next-generation sequencing. We performed CAGE on 97 frozen tissues from surgically resected lung cancers (22 SCC and 75 AD), and confirmed the findings by immunohistochemical analysis (IHC) in an independent group (29 SCC and 45 AD).
Using the genome-wide promoter activity profiles, we confirmed that the expression of known molecular markers used in IHC for SCC (CK5, CK6, p40 and desmoglein-3) and AD (TTF-1 and napsin A) were different between SCC and AD. We identified two novel marker candidates, SPATS2 for SCC and ST6GALNAC1 for AD, as showing comparable performance and complementary utility to the known markers in discriminating PDSCC and non-lepidic AD. We subsequently confirmed their utility at the protein level by IHC in an independent group.
We identified two genes, SPATS2 and ST6GALNAC1, as novel complemental biomarkers discriminating SCC and AD. These findings will contribute to a more accurate diagnosis of NSCLC, which is crucial for precision medicine for lung cancer.
Hermansky–Pudlak syndrome (HPS) is a hereditary disorder involving the sorting processes of intracellular organelles such as lysosomes of reticuloendothelial cells. Pale ear (ep) mouse is known to ...have the HPS1 gene mutation, which is seen in patients with HPS and pulmonary fibrosis. As pulmonary fibrosis is not spontaneously observed in ep mice, we hypothesized that external stimuli are necessary for the genetic predisposition of its development. We used silica as the external stimulus to induce the alveolar macrophage‐mediated inflammatory response and evaluated the pathological changes of the lung and biochemical analysis of collagenolytic lysosomal enzymes cathepsins L and B in ep mice. Treatment with silica induced the following: persistent accumulation of activated macrophages; delayed clearance of silica from alveolar spaces; and increased collagen fibers in alveolar tissues, which were shown with trichrome staining in ep mice. The comparison of bronchoalveolar lavage cells between the naïve ep and control mice revealed: decreased enzymatic activities but increased antigenic levels of cathepsins L and B, resulting in significantly lower ratios of activity to antigen; increased ceroid deposits and cathepsin L antigens in lysosomes; and no abnormal forms of cathepsins were detected. After silica instillation, activities of cathepsin L in the ep mice increased but ratios of activity to antigen were still significantly low. These phenomena induced by silica suggest that external stimuli bring forth fibrogenesis in the animal models or humans that have HPS1 gene mutation.
Here, we present a case of non–small cell lung carcinoma (NSCLC) with widespread and strong nuclear immunopositivity for both thyroid transcription factor-1 (TTF-1) and ΔNp63/p40 (p40). Double ...immunofluorescence for TTF-1 and p40 showed coexpression of both markers in the tumor cells. Furthermore, PTEN (pHis123Asp) and TP53 (pVal272Leu) mutations were identified as possible mitogenic driver mutations by next-generation sequencing. To the best of our knowledge, this is the first case of NSCLC harboring concurrent PTEN and TP53 mutations with widespread and strong coexpression of TTF-1 and p40, which has been confirmed in the resected specimen, and only the second documented case of NSCLC with TTF-1 and p40 diffuse coexpression in the carcinoma cells from the same individual. Our case illustrates the possibility that poorly differentiated NSCLCs with widespread and strong nuclear positivity for TTF-1 and p40 may be an underrecognized and new entity.
•A case of NSCLC with diffuse and strong immunopositivity for both TTF-1 and p40.•This case harbored concurrent PTEN and TP53 mutations.•NSCLCs with these biomarker combinations might be an underrecognized and new entity.
Lenvatinib has been approved for treating various cancers; however, it exerts numerous adverse effects. Hochuekkito, a Japanese Kampo medicine, can alleviate these adverse effects. Here, we aimed to ...evaluate the effect of Hochuekkito on lenvatinib-induced chronic fatigue in a murine model. BALB/C mice were fed a control diet or a diet supplemented with 1.5% Hochuekkito for six weeks. On days 15–42, the mice were intraperitoneally injected with dimethyl sulfoxide or lenvatinib. Accordingly, the mice were divided into control/dimethyl sulfoxide, control/lenvatinib, 1.5% Hochuekkito/dimethyl sulfoxide, and 1.5% Hochuekkito/lenvatinib groups. Body weight and food intake were recorded daily. Nesting tests were performed once a week, and the serum interleukin-6 (IL-6) concentration was measured. Liver drug-metabolizing enzyme, CYP3A4, breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp) levels were determined. The serum lenvatinib concentration and CYP3A4, BCRP, and P-gp levels did not differ significantly between the control/lenvatinib and 1.5% Hochuekkito/lenvatinib groups. The usage rate of nesting material on day 42 was higher in the 1.5% Hochuekkito/lenvatinib group than in the control/lenvatinib group (p < 0.05). The serum IL-6 level was lower in the control/dimethyl sulfoxide and 1.5% Hochuekkito/lenvatinib groups than in the control/lenvatinib group (p < 0.05). Overall, Hochuekkito may alleviate lenvatinib-induced fatigue through IL-6 inhibition.
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