Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type, with Primary Manifestation as an Upper Eyelid Swelling.

Extranodal natural killer/T-cell lymphoma (ENK/TCL) is most often in the nose or the nasopharynx but can present elsewhere. We report a rare case of ENK/TCL that presented as swelling of an upper eyelid without ocular involvement. A 76-year-old man visited our hospital with a swollen lesion of the left upper eyelid which had appeared 2 months earlier. A biopsy of the upper eyelid revealed slight perivascular and periadnexal infiltration of mononuclear cells with dermal edema. Treatment with oral prednisolone at a dosage of 20 mg/day decreased the eyelid swelling. However, 5 months later, exacerbation of the swelling and nasal congestion were observed. A second biopsy of the upper eyelid revealed a diffuse dermal infiltrate composed of mononuclear cells with an angiocentic growth pattern. Immunohistochemical studies and in situ hybridization showed natural killer-lineage antigens (CD56, granzyme B, and T-cell intracellular antigen 1) with expression of Epstein-Barr virus. These findings lead to the diagnosis of ENK/TCL. We treated the patient with radiation therapy (50 Gy) and 3 courses of a regimen including dexamethasone, carboplatin, etoposide, and ifosphamide. This case suggests that ENK/TCL can present with swelling of an upper eyelid as the primary sign of the skin lesion. Swelling of an upper eyelid should be considered in the differential diagnosis of ENK/TCL.

Lupus nephritis class I accompanied by tubulointerstitial nephritis with marked T-lymphocyte infiltration in an HTLV-1 positive patient.

We herein describe the case of a 40-year-old Japanese male who was admitted to our hospital because of a continuous remittent fever lasting 1 month. He fulfilled the items of the classification criteria for the diagnosis of systemic lupus erythematosus (SLE). The administration of 20 mg per day of oral prednisolone completely diminished his clinical symptoms. However, his renal biopsy performed 1 day after the admission showed marked pathognomonic characteristics. Not only did his glomeruli show class I lupus nephritis with mesangial depositions of IgG, IgA, C3, and C1q, but also tubulointerstitial nephritis with marked T-lymphocyte infiltration. These infiltrated T cells partly had nuclear atypia. The patient was positive for human T cell leukemia virus type 1 (HTLV-1) antibodies. Furthermore, clonal rearrangements of T cell receptor-gamma chain gene was detected in the DNA extracted from his kidney sections by the polymerase chain reaction (PCR) method. A second renal biopsy 6 months after the prednisolone treatment showed that the infiltrating T lymphocytes had markedly diminished. This is the first case report of lupus nephritis class I with tubulointerstitial nephritis, which might include oncogenic T lymphocytes, in an HTLV-1 positive patient.

A pathological study of bamboo nodule of the vocal fold.

We examined pathologically a bamboo nodule of the vocal fold by means of immunohistochemical studies and scanning electron microscopic examination. A 38-year-old female showed a high index of antinuclear antibodies without any systemic symptoms but had complained of progressive voice disorder for 9 months. She had used her voice excessively in her occupation and for singing. Hematoxylin and eosin staining showed submucosal edema with lymphocyte and neutrocyte infiltrations and hyaline degeneration. Periodic acid methenamine silver staining showed hypertrophy of the basal lamina of the blood vessels. Immunohistochemical study showed IgG-positive cells in the blood vessel walls. Scanning electron microscopic study demonstrated immune complexes deposited as fine granules of high electrodense materials in the hypertrophic walls of the micro-blood vessels. After surgical resection of the bamboo nodules and advising her to avoid using her voice excessively, her voice improved gradually and the levels of IgG, immune complexes, and antinuclear antibody decreased for 1 year. These findings suggest that the bamboo nodules were not induced by an organ-specific reaction to an autoimmune disease, but mechanical damage to the micro-blood vessels induced by phonation injury of the vocal fold might have caused the deposit of high-molecular weight immune complexes in the damaged micro-blood vessels at the midportion of the vocal folds, which induced secondary inflammatory change at the midportion of the vocal fold.

A case of a mesenteric cyst in the sigmoid colon of a 3-year-old girl.

Mesenteric cysts are rare. In this paper we present a case of a mesenteric cyst in the sigmoid colon of a 3-year-old girl. On the first visit to our department, a smooth-surfaced soft mass approximately 15 cm in diameter was noticed in the right lower abdomen. Although the patient complained of lower abdominal pain, there was no tenderness or guarding. Laboratory tests indicated no abnormality except a slightly increased level of C-reactive protein (2.3 mg/dL). A plain abdominal X-ray film revealed displacement of colonic gas from the right lower abdomen, and abdominal ultrasonography and computed tomography revealed a smooth cystic mass measuring 9.5 x 8.7 x 4.7 cm that contained many internal septa. Because the patient had several symptoms, we performed a surgical operation under general anesthesia. We found a light-red cystic mass, 8.5 x 8.0 x 3.0 cm in size, in the mesentery of the sigmoid colon and surrounding the sigmoid colon, without adhesion to any other organ. We approached the cystic mass from the sigmoid colon and the mesentery of sigmoid colon and completely resected it without complications. The content of the cystic mass was a pale-yellow serous fluid. A cytological examination revealed mainly lymphocytes with reactive mesothelial cells. The resulting pathological diagnosis was a multi-lobular mesenteric cyst. Immunohistochemical staining with D2-40 antibody was positive value along the wall of the cyst, indicating that the cyst was derived from a lymphatic vessel.

Prognosis of glioma patients by combined immunostaining for survivin, Ki-67 and epidermal growth factor receptor.

To confirm that survivin expression is a sensitive marker for the prognosis of glioma patients, surgically resected tissues of ninety-nine Japanese glioma patients using antibodies against survivin, Ki-67 and epidermal growth factor receptor (EGFR) were examined immunohistochemically. The median survival of patients with high survivin expression was significantly shorter than that with low expression (322 vs. 1084 days). Ki-67 expression was significantly associated with that of survivin, whereas no significant association between survivin and EGFR expressions was observed. Patients with low EGFR and low survivin expression survived longer than patients with high EGFR and low survivin expression (1509 vs. 795 days). These results indicate that survivin is a highly sensitive marker for glioma prognosis and suggest that the expression levels of survivin and other markers combined, including EGFR, might be a potent tool for the clinical prognosis of glioma patients.

[A case of Creutzfeldt-Jakob disease with codon 129 polymorphism and codon 180 point mutation].

We report a 79-year-old Japanese man with histlogically-diagnosed Creutzfeldt-Jakob disease (CJD) with codon 129 polymorphism and codon 180 point mutation. At the time of the first examination, we diagnosed and treated as Alzheimer's disease with cerebrovascular disease because of laterality of cortex accumulation and an accumulation decrease of perforating branch areas at the SPECT ((123)I-IMP). His status rapidly progressed to an apallic state and died of lung abscess 12 months later. None of the members of his family had neuromuscular disorders. EEG (electroencephalogram) did not reveal periodic synchronous discharges (PSD). Prion protein gene analysis showed Codon 129 polymorphism (Met/Val) and codon 180 point mutation (Val/Ile). The autopsy findings revealed spongiform changes and numerous senile plaque formation in the cerebral cortex. The hippocampus and the cerebellar cortex were well preserved and did not show lacunar infarctions. CJD patients with combination of the codon 180 point mutation and codon 129 polymorphism of the PrP gene have rarely been reported.

Profiling of fluorouracil-related genes by microdissection technique in hepatocellular carcinoma.

BACKGROUND/AIMS: 5-fluorouracil (5-FU)-related metabolic enzymes, including dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS), thymidylate phosphorylase (TP), and orotate phosphoribosyl transferase (OPRT) are initial, rate-limiting enzymes in the metabolism of 5-FU. The therapeutic implications of these enzymes in hepatocellular carcinoma (HCC) remain poorly understood. We used a newly developed laser-captured microdissection technique combined with RNA extraction to examine the mRNA levels of 5-FU-related metabolic enzymes in HCC and adjacent liver tissue. METHODOLOGY: The study material comprised 43 paired specimens of HCC and adjacent liver tissue. The mRNA levels of 5-FU-related metabolic enzymes were quantified by real-time reverse-transcriptase polymerase chain reaction combined with laser-captured microdissection. RESULTS: The DPD mRNA level in HCC (4.31 +/- 4.21) was lower than that in adjacent liver (6.53 +/- 2.93) (p < 0.001). The TS mRNA level in HCC (3.55 +/- 2.54) was higher than that in adjacent liver (1.90 +/- 0.11) p < 0.001). The TP and the OPRT mRNA levels did not differ significantly between HCC and adjacent liver. The TS mRNA level of HCC with portal invasion (4.47 +/- 2.76) was higher than that of HCC without portal invasion (2.71 +/- 1.96) (p = 0.015). The DPD mRNA level of HCC with septum formation (4.89 +/- 4.82) was significantly higher than that of HCC without septum formation (2.12 +/- 0.61) (p < 0.027). The OPRT mRNA level of poorly differentiated HCC (1.18 +/- 0.49) was lower than that of moderately or well-differentiated HCC (2.42 +/- 1.82) (p = 0.037). CONCLUSIONS: The DPD mRNA level was lower and the TS mRNA level was higher in HCC than in adjacent liver. Our results will hopefully stimulate further investigations designed to optimize the use of 5-FU in patients with HCC.

[A case of elderly metastatic breast cancer with a complete response to treatment with capecitabine and cyclophosphamide].

We report a case of elderly metastatic breast cancer with a complete response to the treatment with XC (X: capecitabine and C: cyclophosphamide). A 78-year-old woman, who presented with left breast cancer, underwent pectoralis-preserving mastectomy when she was 76 years old. Pathological findings were as follows: invasive ductal carcinoma (scirrhous type), pT1c (2.0 cm), n (1/10), ly3, v1, ER (-), PgR (-), HER2: score 1. After one year and a half, a left supraclavicular lymph node metastasis, a left interpectoral lymph node metastasis, and mediastinal lymph nodes metastasis were noted. Capecitabine and cyclophosphamide were administered as first-line chemotherapy. After 8 cycles, all metastases responded, and this therapy is now being continued (19 cycles) on an outpatient basis. The complete response has continued for nine months. XC therapy can be the first-line chemotherapy for elderly metastatic breast cancer patients since it has been effective and no serious side effects have been encountered while maintaining quality of life.

Role of matrix metalloproteinases and their tissue inhibitor of metalloproteinases in myxomatous change of cardiac floppy valves.

To clarify the underlying cause of myxomatous changes in cardiac floppy valves, the expression of the matrix metalloproteinases (MMP) and the tissue inhibitors of metalloproteinases (TIMP) was investigated in cardiac valves. Valves were obtained from nine patients with floppy valves, from 13 patients with other valvular disease types, and from four patients with normal valves. Immunohistochemical analyses for MMP-2, MMP-9, TIMP-1, and TIMP-2, and gelatin zymography for MMP-2 and MMP-9 were performed. Compared with the spongiosa of normal valves, the myxomatous area of floppy valves had stronger immunohistochemical reaction to MMP-2 and MMP-9, and weaker reaction to TIMP-2. Activated MMP-2 and MMP-9 were detected in eight out of nine cases of floppy valves. Activated MMP-2 was detected at low levels in two cases of normal valves showing mild expansion of the spongiosa without macroscopic floppiness. The ratio of active/total MMP-2 and MMP-9 increased in floppy valves compared with normal valves. These results suggest that the imbalance between MMP and TIMP and the increased activity of MMP-2 and MMP-9 may correlate with myxomatous changes observed in floppy valves. Valves with a slight myxomatous change and activated MMP-2 may develop into floppy valves with increases in the activity of MMP.

Helicobacter pylori infection-negative gastric cancer in Japanese hospital patients: incidence and pathological characteristics.

We used Helicobacter pylori sero-positivity and mucosal atrophy as detected by the serum pepsinogen method to identify H. pylori infection-negative gastric cancer patients with or without atrophy. One hundred and six of 748 (14.2%) primary gastric cancer patients were infection-negative by a serum antibody detection system. Further, 121 (16.2%) of the 748 were negative for gastric mucosal atrophy by the pepsinogen method, of whom 15/748 (2.0%) were H. pylori-negative by pepsinogen I level (>70 ng/mL) and pepsinogen I/II ratio (>3.0). Twenty-seven of 782 (3.6%) gastric cancer patients were H. pylori-negative by antibodies and severe atrophy as determined by pepsinogen I level (<30 ng/mL) and pepsinogen I/II ratio (<2.0). H. pylori-negative gastric cancer patients with severe atrophy likely had a previous infection. These results indicate that the actual number of H. pylori-negative patients is 2.0% at minimum and 10.6% (14.2% minus 3.6%) at maximum in the general Japanese population. Five of 15 (33%) cases displaying neither anti-H. pylori antibodies nor atrophy were intestinal-type and 10 (67%) were diffuse-type adenocarcinomas. Thirteen surgical patients with primary gastric cancer displaying neither antibodies nor mucosal atrophy were further analyzed for pathological and phenotypic characteristics. The mucin phenotype was divided into four gastric, five gastric and intestinal, two intestinal and two null types, independent of histological classification. Intestinal phenotype elements were detected by Cdx2 immunohistochemical methods in nine of 13 (70%) cases examined. We conclude that a small fraction of gastric cancer patients displayed multifactorial carcinogenesis without H. pylori infection, indicating that gastric cancer risk still exists in the absence of H. pylori infection, at an incidence of 2.0% at minimum and 10.6% at maximum in the general Japanese population.

Histopathological evaluation of left atrial appendage thrombogenesis removed during surgery for atrial fibrillation.

BACKGROUND: In this study, we histopathologically assessed left atrial appendages (LAAs) resected during surgical treatment for atrial fibrillation (AF) to elucidate the mechanism of intra-LAA thrombus formation in valvular AF. METHODS: The clinicopathological study of resected LAA was made on 56 valvular AF cases: 28 with mitral regurgitation (MR), 3 with mitral stenosis, and 25 with mitral stenosis and MR. Pathological findings of thrombi in LAA were compared with clinical features, including history of valvular diseases and embolism, and findings of echocardiography. Results were analyzed using chi2 test, Fisher exact method, or Welch t test. RESULTS: Two types of mural thrombi were found in LAA: membranous (M)-thrombi and polypoid-shape (P)-thrombi. M-thrombi were found on LAA endocardium in 48 (86%) patients. All of the P-thrombi were observed on preexisting M-thrombi. More patients showed thrombi in the LAA orifice than in the tip (P < .001), especially in cases of MR (21 patients; P < .01). By echocardiography, MR flow was classified into 3 directions: toward the roof, anteroseptal, or posterolateral wall of the left atrium. Patients with MR jet flow against the posterolateral wall near the LAA entrance had a higher risk of LAA thrombi (P = .007). CONCLUSIONS: Instability of M-thrombi, including surface rupture before complete organization, relates to P-thrombi formation that results in high incidence of embolism in AF patients.

Histopathological features of the resected left atrial appendage as predictors of recurrence after surgery for atrial fibrillation in valvular heart disease.

BACKGROUND: A histopathological assessment of left atrial appendages (LAA) resected during surgical treatment for atrial fibrillation (AF) was made, with the aim of improving the prediction of postoperative AF recurrence. METHODS AND RESULTS: This clinicopathological study involved 57 surgical cases of valvular AF and 34 age- and sex-matched control autopsy cases with a history of sinus rhythm. LAA from the cases with valvular AF showed greater hypertrophy of cardiomyocytes (p<0.0001), greater nuclear enlargement (p<0.0001), more bizarre nuclei (BN; p<0.0001), and more intercellular fibrosis (ICF; p<0.001). Partial disarray of cardiomyocytes and fatty infiltration were recognized in both the AF and control groups. Thirty-seven cases had maintained sinus rhythm after surgery from 7 months to 10 years. AF recurred within a month of surgery in 17 and after a month in 3; there was no significant difference in histopathological features between them. These 20 cases had more cellular hypertrophy (p<0.025), nuclear enlargement (p<0.025), BN (p<0.01), and ICF (p<0.025) than those who maintained sinus rhythm after surgery. CONCLUSIONS: The histopathological findings for LAA reflected the underlying valvular diseases; however, the most reliable predictors of postoperative AF recurrence were hypertrophy of cardiomyocytes, bizarre shaped nuclei, and extensive ICF.

Significance of noninvasive diagnosis of prostate cancer with cytologic examination of prostatic fluid.

OBJECTIVES: While reassessing the value of exfoliative cytologic examination of prostatic fluid (PF) for the diagnosis of prostate cancer, we found that PF is easily obtained with transrectal ultrasonography during prostate biopsy and that cytologic examination of PF is useful for the diagnosis of prostate cancer. METHODS: The cohort included 53 consecutive patients who underwent transrectal prostate biopsy from May through September 2005. Patient age was 66.7 +/- 7.24 years, and the mean concentration of prostate-specific antigen (PSA) was 15.1 +/- 25.8 ng/ml. The PF for cytologic examination was obtained before biopsy, and Papanicolaou's staining was performed. The results of cytologic examination are expressed as class 1 to 5. Results of cytologic examination and prostate tissue pathologic examination were analyzed. Patient age, PSA levels, total prostate volume (TPV), and PF volume were compared with cytologic class by means of analysis of variance. RESULTS: The mean PF volume was 378.4 +/- 245.3 microl, and the mean TPV was 38.0 +/- 18.8 ml. The numbers of patient in classes 1 to 5 were 1 (1.9%), 37 (69.8%), 11 (20.7%), 1 (1.9%), and 3 (5.7%), respectively. Pathologic examination showed 23 (43.4%) cases of cancer, 27 (50.9%) cases of benign prostatic hyperplasia, and 3 (5.7%) cases of high-grade prostatic intraepithelial neoplasia. All three patients with class 5 results had prostate cancer (Gleason score, 7 to 10). All 9 patients with a PSA level greater than 16 ng/ml had biopsy-proven cancer, and 3 of these 9 patients (33.3%) were in cytology class 5. Therefore, PF cytologic examination showed a specificity of 100% and a sensitivity of 33.3% in patients with PSA levels higher than 16 ng/ml. The cytologic classes differed in PSA levels (F=8.271, P=0.000) but not in patient age, TPV, or PF volume. CONCLUSIONS: Exfoliative cytologic examination of PF is a valuable, noninvasive method for detecting prostate cancer, especially in patients with high PSA levels.

Cyclooxygenase-2 expression correlates with membrane-type-1 matrix metalloproteinase expression in colorectal cancer tissue.

PURPOSE: Elevated expression of cyclooxygenase-2 has been found in colorectal cancer. One of the mechanisms through which cyclooxygenase-2 affects tumorigenesis is through its overexpression, which leads to increased invasiveness of cancer cells. A crucial step in this pathway is thought to be the induction of membrane-type-1 matrix metalloproteinase, which activates matrix metalloproteinase-2. However, to date there have been few clinicopathologic studies concerning cyclooxygenase-2-mediated invasiveness in human colorectal cancer tissues. METHODS: We performed immunohistochemical analysis of the respective antigens on colorectal cancer specimens obtained by surgical resections from 96 patients with colorectal cancer. RESULTS: Cyclooxygenase-2 and membrane-type-1 matrix metalloproteinase expression was positive exclusively in cancer cells in 88 cases (92 percent) and 23 cases (24 percent), respectively. All 23 cases expressing membrane-type-1 matrix metalloproteinase also expressed cyclooxygenase-2. Matrix metalloproteinase-2 expression was positive in cancer cells in 20 cases (21 percent) and stromal cells in 52 cases (54 percent). Expression of matrix metalloproteinase-2 in cancer cells correlated with lymphatic invasion and local recurrence. Statistically, a significant correlation was found between cyclooxygenase-2 and membrane-type-1 matrix metalloproteinase expression, and membrane-type-1 matrix metalloproteinase and matrix metalloproteinase-2 expression in cancer cells. There was no association between cyclooxygenase-2 expression and matrix metalloproteinase-2 expression. However, immunostaining of serial sections revealed that in the majority of cases examined, nearly 100 percent of cancer cells expressing matrix metalloproteinase-2 also coexpressed cyclooxygenase-2. CONCLUSIONS: This study indicates strong association between both cyclooxygenase-2 and membrane-type-1 matrix metalloproteinase expression, and membrane-type-1 matrix metalloproteinase and matrix metalloproteinase-2 in colorectal cancer. These results support our thesis of a direct correlation between cyclooxygenase-2 and membrane-type-1 matrix metalloproteinase expression--with consequent association between cyclooxygenase-2 and matrix metalloproteinase-2 activation, and tumor invasiveness andrecurrence in certain cases of colorectal cancer.

Identification of histological markers for malignant glioma by genome-wide expression analysis: dynein, alpha-PIX and sorcin.

Glioblastoma multiforme (GBM), the most malignant class of glial neoplasm (grade IV in WHO criteria), carries the worst clinical prognosis among primary brain tumors in adults. To identify a set of genes involved in the tumorigenesis of GBM, we evaluated expression profiles of GBM tissues from 11 patients using a cDNA microarray representing 25,344 human genes. By comparing the profiles with those of normal brain tissue, we identified a number of differentially expressed genes: 54 with increased expression and 45 with reduced expression in GBMs. Semi-quantitative RT-PCR experiments with 6 of those genes confirmed higher expression of DNCH2, ARHGEF6, NPM1 and SRI and lower expression of NRGN and TM4SF2 in GBM tumors. Immunohistochemical staining for 3 of the respective gene products, dynein (product of DNCH2), alpha-PIX (product of ARHGEF6), and sorcin (product of SRI) indicated that this technique might be useful for histological grading of glial tumors. To establish criteria for this diagnostic approach, we scored glial tumor tissues of different histological grades according to the staining results; the scores were significantly higher in anaplastic astrocytomas and GBMs than in diffuse astrocytomas or normal brain tissues. These findings indicated that levels of these three proteins might serve as histological markers for malignant glioma classification.

Occurrence of hyaline droplets in renal biopsy specimens: an ultrastructural study.

Hyaline droplets are apical cytoplasmic vesicles containing an accumulation of electron-dense amorphous materials surrounded by a unit membrane. Hyaline droplets may originate from apical vesicles after conversion to osmotic vesicles and loss of internally lined glycocalyx. They are found in the proximal tubular epithelium in biopsies from patients with renal diseases; however, their biological importance is not well understood. We reviewed ultrastructural pathology records of 140 renal biopsy patients to determine the occurrence and relevance of hyaline droplets. Of the cases, 14 (10%) showed the presence of hyaline droplets in proximal tubular epithelium. The distribution of cases were 8 of the 19 (42%) with minimal change nephritic syndrome, 2 of the 37 (5%) with IgA nephropathy, 2 of the 4 (50%) with membranous glomerulonephropathy, 1 of the 4 (25%) with tubulointerstitial nephritis, and 1 of the 1 (100%) with acute renal failure. The droplets were frequently found in male patients (86%), never in children, and were mostly associated with tubular necrosis (8 of 14 cases; 56%). Many hyaline droplets were observed in the cytoplasm of necrotic proximal tubular epithelial cells, and even when tubular necrosis was not evident, the proximal tubular epithelial cells containing hyaline droplets showed degenerated microvilli and decreased basal interdigitations. These results suggest that hyaline droplets could be one marker of renal tubular necrosis and a sign of functional disorder of protein reabsorption by degenerating proximal tubular epithelium.

Histopathological study of tissue reaction to pacemaker electrodes implanted in the endocardium.

Limited information is available about histopathological reactions to the implanted endocardial electrodes of pacemakers (PM). Gross anatomic and histologic studies of tissue reactions to PM electrodes were made in thirteen autopsy cases (nine men and four women, ages 25 approximately 89 years, mean age 71.8) who died two months to twenty-one years after PM implantation. Nine of them had complete atrioventricular (AV) block, three had sick sinus syndrome, and one had bradycardia-tachycardia syndrome. The direct causes of death were not related to their PM. The tip with projecting tines was implanted in the right ventricle in all patients. At the contact area between the electrode and the endocardium, no tissue reaction was observed in one patient with a history of over sixteen years of PM implantation. However, cardiomyocytes under the tip had been replaced by fibrotic tissue in many other patients. In two patients in particular where the electrode had been implanted at the apex of each right ventricle, all cardiomyocytes had disappeared and only fibrotic tissue and adipose tissue were observed under the tip. These findings suggest that mechanical stress caused by attaching the tip tightly damages cardiomyocytes and brings about changes in the pacing thresholds. In three patients, a space was seen between the tip and the endocardium. A fibrous sheath covering the electrode extended to the tip and formed a thick fibrous cap. This non-excitable fibrous cap acted as a virtual electrode and possibly affected the elevation of the threshold in these patients. In four patients, extensive myocardial fibrosis due to disease, e. g. previous myocardial infarction, dilated cardiomyopathy, amyloidosis, or sarcoidosis, was found in the area surrounding the tip and also might affect the elevation of the threshold. We concluded that elevation of pacing thresholds after PM implantation is not due to reactive endocardial thickening. The space between the tip and the endocardium is occupied by a fibrous sheath, and an overly tight attachment damages cardiomyocytes causing replacement fibrosis. Thus, it is not desirable in some patients to insert the electrodes into the apex, where the myocardium is thin. To avoid the elevation of thresholds, development of further devices is necessary to allow electrode fixation to the endocardium with a more suitable pressure level.