Colitis with Hypereosinophilia following the Second Dose of the BNT162b2 mRNA COVID-19 Vaccine: A Case Report with a Literature Review.

A 61-year-old man presented with a 7-day history of watery diarrhea and loss of appetite after receiving the second dose of the Pfizer-BioNTech COVID-19 vaccine. Laboratory studies showed significant eosinophilia and an elevated IgE level (white cell count, 18.4×109/L; eosinophil count, 9.5×109/L; and IgE level, 540 IU/L). Symptoms resolved 10 days after vaccination without any steroids or antiallergic medications, and the eosinophil count had also returned to within normal limits 2 months later. Several cases of eosinophilic disorders following receipt of any type of injectable COVID-19 vaccine have been reported, so the etiology should be examined.

Muscular metastasis of superficial esophageal squamous cell carcinoma: a rare case of recurrence after endoscopic submucosal dissection with additional chemoradiotherapy.

Esophageal cancer after endoscopic treatment may recur depending on the risk. We present a case of a rare T1b esophageal cancer after endoscopic treatment plus chemoradiotherapy (CRT) that recurred with metastasis of the dorsal muscles. A 70-year-old man was referred for treatment of early-stage esophageal carcinoma. Endoscopic submucosal dissection (ESD) was performed and histopathology showed a poorly differentiated squamous cell carcinoma with invasion to the submucosal layer (sm2) with INFc-type invasion and positive venous invasion. After subsequent CRT, the patient was monitored every 6 months, using computed tomography (CT) and endoscopy. Fifteen months after the treatment, contrast CT revealed a spherical mass with 9 cm ring enhancement within the right erector spinae, that had squamous cell carcinoma confirmed by CT-guided biopsy. Radiation and systemic chemotherapy were initiated for the metastasis of the esophageal carcinoma. However, he died of respiratory failure due to rapid pleural effusion 26 months after ESD. Pathological autopsy showed diffuse squamous cell carcinoma invasion of the cystic wall, forming a lumbar mass, and absence of cancer cell remnants or recurrences in the esophagus. This case report emphasizes the need for systemic observation of superficial esophageal cancer after treatment with a high risk of recurrence.

Anti-nuclear antibody and a granuloma could be biomarkers for iCIs-related hepatitis by anti-PD-1 treatment.

It has been reported that various kinds of immune checkpoint inhibitors (iCIs) could induce immune-related liver damage. We should focus on the programmed cell death-receptor-1 (PD-1) antibody and non-small cell lung cancer (NSCLC) to analyze the characteristics of hepatitis related to iCIs and find factors that could be useful biomarkers for the diagnosis. A single-center retrospective study of 252 NSCLC patients who received PD-1 antibody (nivolumab or pembrolizumab). Some of the biochemical markers and immunological markers were analyzed during PD-1-antibody treatment with or without ALT elevation. Histopathological features were reviewed by a single expert of hepatic pathology focusing on the following features: fibrosis, portal inflammation, lobular inflammation, lobular necrosis. The formation of macro- and micro-granulomas was also evaluated. The frequency of liver damage induced by nivolumab including grade 1 to 4 (ALT) was 41.9% (78/186 patients). The positive rate of anti-nuclear antibody in the nivolumab group with iCIs-related hepatitis was significantly higher than that in the nivolumab group without iCIs-related hepatitis (p = 0.00112). Granulomatous changes were significantly increased in patients with iCIs-related hepatitis compared with DILI and AIH patients (p < 0.05). The ratios of inflammatory cells CD4/CD8, and CD138/CD3 in ICIs-related hepatitis were significantly lower than those in AIH or DILI patients (p < 0.05). We demonstrated that the pre-existing ANA and characteristic liver histology including CD8+ cells dominancy and granulomatous hepatitis could be biomarkers for the diagnosis of iCIs-related hepatitis in the NSCLC with anti-PD-1 therapy.

Suppression of tumor immune microenvironment via microRNA-1 after epidermal growth factor receptor-tyrosine kinase inhibitor resistance acquirement in lung adenocarcinoma.

Immunotherapy is considered one of the most important therapeutic strategies for patients with lung adenocarcinoma after the development of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. However, useful predictors of immunotherapy for these patients has not been examined well, although the status of the tumor immune microenvironment (TIME), including programmed death-ligand 1 expression and lymphocyte infiltration, has been generally known to provide predictive markers for the efficacy of immunotherapy. This study aimed to clarify novel predictors of immunotherapy following EGFR-TKI resistance in lung adenocarcinoma, especially regarding micro RNA (miRNA). We evaluated the correlation between EGFR-TKI resistance and lymphocyte infiltration, before and after acquiring EGFR-TKI resistance, in 21 cases of lung adenocarcinoma, and further explored this by in vitro studies, using miRNA PCR arrays. Subsequently, we transfected miRNA-1 (miR-1), the most variable miRNA in this array, into three kinds of lung cancer cells, and examined the effects of miR-1 on EGFR-TKI sensitivity, cytokine expression and lymphocyte migration. Histopathological examination demonstrated that infiltration levels of CD8-positive T cells were significantly decreased after development of EGFR-TKI resistance. In vitro studies revealed that miR-1 significantly inhibited EGFR-TKI effect and induction of cytokines, such as C-C motif chemokine ligand 5 and C-X-C motif chemokine ligand 10, causing inhibition of monocyte migration. These results indicate that the upregulated miR-1 might suppress the TIME, following development of EGFR-TKI resistance. Therefore, miR-1 could be a clinically useful marker to predict therapeutic efficacy of immunotherapy in lung adenocarcinoma patients with EGFR-TKI resistance.

Preoperative predictors of lymph node metastasis in clinical T1 adenocarcinoma.

BACKGROUND: The subcategory "solid component of tumor" is a new criterion of tumor categories in the updated eighth edition of the TNM classification. Nevertheless, the predictors of lymph node metastasis among patients with clinical T1 adenocarcinoma, based on the TNM classification 8th edition, remain unclear. This study aimed to identify the preoperative predictors of lymph node metastasis in clinical T1 adenocarcinoma by comparing clinicopathological characteristics between the groups with and without lymph node metastasis. METHODS: We performed a retrospective observational single-center study at the Sendai Kousei Hospital. From January 2012 to September 2019, we included 515 patients who underwent curative lobectomy or segmentectomy and mediastinal lymph node dissection among those with clinical T1 adenocarcinoma according to the UICC-TNM staging 8th edition. They were divided into two groups: those with lymph node metastasis (positive group) and those without (negative group). The clinicopathological factors were retrospectively analyzed and compared between the groups. RESULTS: In univariate analysis, carcinoembryonic antigen (>5.0 ng/mL) (P=0.0007), maximum standardized uptake (>3.5) (P<0.0001), clinical T factor (T1c) (P<0.0001), and consolidation tumor ratio (>0.85) (P<0.0001) were significant predictors of lymph node metastasis. Multivariate analysis revealed that maximum standardized uptake SUVmax (>3.5) (odds ratio =10.4, P<0.0001) was independently associated with lymph node metastasis. In univariate analysis, carcinoembryonic antigen (>5.0) (P=0.048) was the only predictor of lymph node metastasis among patients of cT1b, while no parameters were identified as significant predictors among patients of cT1c. CONCLUSIONS: SUVmax and CEA are useful preoperative predictors of lymph node metastases in patients with clinical T1 adenocarcinoma, stratified to T1b and T1c, based on the 8th TNM classification.

Consensus molecular subtypes classification of colorectal cancer as a predictive factor for chemotherapeutic efficacy against metastatic colorectal cancer.

The consensus molecular subtypes (CMS) classification is one of the most robust colorectal cancer (CRC) classifications based on comprehensive gene expression profiles. This study aimed to clarify whether the CMS is a predictive factor for therapeutic effects of standard chemotherapies for metastatic CRC (mCRC). We retrospectively enrolled 193 patients with mCRCs, and using comprehensive gene expression data, classified them into 4 subtypes: CMS1-CMS4. The associations between the subtypes and treatment outcomes were analyzed. Regarding first-line chemotherapy, irinotecan (IRI)-based chemotherapy was significantly superior to oxaliplatin (OX)-based chemotherapy for progression-free survival (PFS; hazard ratio [HR] = 0.31, 95% confidence interval [CI] 0.13-0.64) and overall survival (OS; HR = 0.45, 95% CI 0.19-0.99) in CMS4. Regarding the anti-epidermal growth factor receptor (anti-EGFR) therapy, CMS1 showed particularly worse PFS (HR = 2.50, 95% CI 1.31-4.39) and OS (HR = 4.23, 95% CI 1.83-9.04), and CMS2 showed particularly good PFS (HR = 0.67, 95% CI 0.44-1.01) and OS (HR = 0.49, 95% CI 0.27-0.87) compared with the other subtypes. The biological characteristics of CMS may influence the efficacy of chemotherapy. CMS might be a new predictive factor for the efficacy of chemotherapy against mCRCs.

Immunoglobulin G4-related constrictive pericarditis identified by cytological examination of pericardial effusion: a case report.

BACKGROUND: Immunoglobulin G4-related disease is increasingly recognized as a systemic autoimmune disorder characterized by immunoglobulin G4-positive lymphocyte infiltration. Organ biopsy and histopathology are the most important diagnostic methods; however, the significance of a cytological examination in immunoglobulin G4-related disease cases is still unclear. CASE PRESENTATION: A 73-year-old Asian man who was a former tobacco smoker presented with progressive exertional dyspnea, systemic edema, and pericardial effusion. A cytological examination of his pericardial effusion detected three or four plasma cells per high-power field by Giemsa staining. Moreover, immunoglobulin G4-positive plasma cells were detected by immunostaining. Cardiac catheterization after pericardiocentesis revealed that both ventricular pressure traces showed an early diastolic dip and plateau. Positron-emission tomography with 18F-fluorodeoxyglucose imaging revealed inflammatory foci in his pericardium. A surgical pericardiectomy was performed and the resultant specimen showed significant immunoglobulin G4-positive plasma cell infiltration and marked fibrous thickening of his pericardium; therefore, a diagnosis of constrictive pericarditis due to immunoglobulin G4-related disease was made. Oral administration of 0.6-mg/kg/day prednisolone resolved his heart failure and he was discharged on foot 1 week later. CONCLUSION: Our experience with this case indicates that cytological examination of pericardial effusion was useful in the diagnosis of immunoglobulin G4-related disease.

A case of a glomus tumor of the stomach resected by laparoscopy endoscopy cooperative surgery.

A 56-year-old woman who was found to have a submucosal tumor (SMT) of the stomach in a medical check-up was admitted to our hospital for a detailed investigation of the SMT. Upper gastrointestinal endoscopy revealed an SMT of 20mm at the anterior wall of the antrum of the stomach. Endoscopic ultrasonography showed a hyperechoic tumor in the fourth layer of the stomach wall. CT examination showed a strongly enhancing tumor on arterial phase images and persistent enhancement on portal venous phase images. Laparoscopy endoscopy cooperative surgery was performed with a diagnosis of SMT of the stomach highly suspicious of a glomus tumor. Immunohistochemistry revealed expression of α-SMA but no expression of desmin, c-kit, CD34, or S-100. The tumor was finally diagnosed as a glomus tumor of the stomach.

Differentiation of pathologic subtypes of papillary renal cell carcinoma on CT.

OBJECTIVE: We reviewed the CT findings of the subtypes of papillary renal cell carcinoma (RCC), which behave differently clinicopathologically. CONCLUSION: The CT features of the two pathologic subtypes of papillary RCC differ, probably reflecting their different pathologic features. Type 1 tumors have more distinct margins than type 2 tumors and have homogeneous density. Although type 2 tumors in the early stages show findings similar to those of type 1 tumors, they are at more advanced stages on the whole, with CT features showing indistinct margins, frequent centripetal infiltration, and tumor thrombi in all pT3b cases. Radiologists should be familiar with the CT features of papillary RCC that suggest different pathologic behaviors, such as tumor stage, tumor proliferation, and microvascular or vascular invasion.

Anterior apical biopsy: is it useful for prostate cancer detection?

OBJECTIVES: To evaluate the utility of a 12-core prostate biopsy protocol including apical anterior peripheral zone (AAPZ) cores. METHODS: Between February 2002 and October 2006, 10-core and 12-core initial transrectal prostate biopsies were performed on 164 and 549 men, respectively. Two AAPZ-directed biopsies were included in the 12-core biopsy. During the same period, 12-core repeat biopsies including six AAPZ sites were performed on 118 men. RESULTS: Cancer was found in 66 cases (40.2%) in the 10-core biopsy group and in 252 (45.9%) in the 12-core biopsy group. In this latter group, 13 (5.2%) of the 252 men with positive biopsy had cancer exclusively in the AAPZ cores. When the cancer detection rate at initial biopsy in AAPZ alone was compared according to the digital rectal examination (DRE) findings, it was significantly higher in men with normal rather than abnormal DRE: 12/250 (3.4%) vs 1/185 (0.5%) (P < 0.01). In repeat 12-core biopsies, cancer was detected in 25 (21.2%) men and 9 of them (36.0%) had cancer exclusively in the AAPZ cores. The cancer detection rate from AAPZ sites was significantly higher in repeat biopsy than that in initial biopsy (P < 0.01). CONCLUSIONS: Addition of the AAPZ site-directed biopsy had greater utility in men with normal DRE and particularly in patients with a prior negative biopsy.

Operative treatment by external fixation for polyostotic fibrous dysplasia in the elbow joint. A case report.

Fibrous dysplasia is a condition in which normal skeletal bone changes into fibroblastic stroma and immature bone. We report our experience of a unilateral external fixator applied for the treatment of polyostotic fibrous dysplasia arising in the elbow. The patient was a 38 year-old man. His main complaint was left elbow pain and a mass, which increased in size. The histological diagnosis from the needle biopsy was fibrous dysplasia. An articulated unilateral external fixator was used for immobilization. The lesions in the left distal humerus and proximal ulna were curetted and cancellous bone was packed into the cavity. An external fixator (Elbow Fixator, Orthofix Inc., McKinney, USA) was applied from the proximal humeral shaft to the distal ulnar shaft for postoperative tentative immobilization and preservation of the affected elbow joint movement. At two years after the operation, the range of motion of the affected elbow was 90 degrees in flexion and -35 degrees in extension. The range of motion in pronation and supination of the left forearm was normal. No evidence of recurrence was noted at two years after surgery. The merits of using an external fixator were: an earlier start of range of motion exercises, and a decrease in the risk of tumor dissemination.

Rapidly growing endobronchial hamartoma with bone marrow tissue.

A 29-year-old woman presented with a 4 x 3.5 cm circumscribed mass located in the left upper lobe, which had not been detected in a chest roentgenogram that was taken 3 years prior. Bone scintigraphy using technetium-99m methylene diphosphonate revealed an increased uptake of the isotope in the mass, indicating increased osteoplastic activity. She underwent surgical resection of the mass and the pathologic diagnosis was endobronchially located pulmonary hamartoma, which contained bone marrow tissue. An extremely rare case of pulmonary hamartoma showing rapid growth and involving bone marrow tissue is presented.

Steroid sulfatase and estrogen sulfotransferase in human prostate cancer.

BACKGROUND: Estrogen sulfotransferase (EST) and steroid sulfatase (STS) are known to be involved in in situ estrogen production in estrogen dependent human cancer such as breast cancer, but unknown in prostate cancer. MATERIALS AND METHODS: We first examined whether these enzymes above were expressed and actually involved in estrogen production and metabolism in prostate cancer cell lines (LNCaP, DU-145, and PC-3). We than examined the expression of EST and STS in human prostate cancer tissues obtained from surgery (n = 52) using immunohistochemistry. RESULTS: mRNAs of both enzymes were detected in all prostate cancer cell lines examined, and the synthesis of estrone (E(1)) and estradiol (E(2)) was also confirmed in these cell lines. In addition, STS immunoreactivity was detected in 44 cases (85%) and EST in 39 cases (75%), respectively. CONCLUSIONS: STS and EST are expressed and may be involved in local production and metabolism of estrogens in human prostate cancers.

Intraoperative, radio-guided sentinel lymph node mapping in laparoscopic lymph node dissection for Stage I testicular carcinoma.

BACKGROUND: The management of regional lymph nodes in patients with clinical Stage I testicular carcinoma is a controversial problem. The authors investigated the feasibility and accuracy of radio-guided mapping of sentinel lymph nodes (SLNs) for men with clinical Stage I testicular tumors. METHODS: Twenty-two patients with clinical Stage I testicular carcinoma were enrolled in the study. One day before surgery, (99m)Technetium-labeled phytate was injected around the testicular tumor. After undergoing radical orchiectomy, patients underwent laparoscopic retroperitoneal lymph node dissection (L-RPLND). All radioactive lymph nodes were marked in the L-RPLND procedure, and three-dimensional SLN maps were made. All resected lymph nodes were evaluated by routine histopathologic examination, and the clinical significance of intraoperative SLN mapping was evaluated. RESULTS: SLNs were detected in 21 of 22 patients (95%). Nearly all SLNs were detected at the ventral or lateral side of the vena cava or at the aorta between the levels of the aortic bifurcation. All SLNs were detected easily in a surgical procedure. Only 1 radio-positive area per patient was identified in 15 patients, and approximately 2-4 positive areas were detected in 6 patients. Two patients had micrometastasis only in SLNs. In 2 patients who had seminoma, lymph node recurrences (at the level of the renal vein and in the obturator lymph node area) occurred at 10 months and 20 months after surgery. CONCLUSIONS: Radio-guided mapping of SLNs with laparoscopy was feasible, and nearly all SLNs were detected accurately by the procedure. In the near future, the standard retroperitoneal lymph node dissection may be avoided in most patients with clinical Stage I testicular carcinoma by utilizing focused examination of SLNs.

[Carcinoma in situ detected by contralateral testicular biopsy of 55 germ cell tumor patients].

PURPOSE: We performed contra-lateral testicular biopsies in 55 testicular tumor patients when high orchiectomy was performed. In these cases, two cases developed invasive testicular tumor later although the biopsies had not revealed testicular CIS. Then we re-examined the sensitivity of biopsies and judged if our results are contradictory against Skakkebaek's theory. PATIENTS AND METHODS: The paraffin blocks of two cases who later developed testicular tumor were sliced again and re-examined by H/E staining and immunostaining with PLAP antibody (clone No. 8A9). The other 53 H/E samples were re-examined and the result of the contra-lateral testis was re-searched in the case that CIS was detected in the specimen. RESULTS: CIS was detected in one of the two cases who later developed contra-lateral testicular tumor and another case among the other 53 cases. We could not reveal the result of the testis of case No. 3 because of the patient's disappearance. CIS existed 3.6% (2/55) and two cases were found to have been false negative. CONCLUSION: It is important for both urologists and pathologists to know well about testicular CIS and to perform biopsy according to Skakkebaek's guidance for raising the sensitivity to detect testicular CIS.

Heterogeneous increase in CD34-positive alveolar capillaries in idiopathic pulmonary fibrosis.

To elucidate the apparent contradictions in vascular remodeling in the lungs of patients with idiopathic pulmonary fibrosis, we evaluated alveolar vascularity in relation to the various degrees of fibrosis in surgically biopsied lungs of usual interstitial pneumonia. Alveolar capillary endothelial cells were intensely immunoreactive with CD34 but not with von Willebrand factor. Vascular density, that is, the relative ratio of capillary area to total area of alveolar walls, was significantly higher at low grades of fibrosis than in control lungs, whereas vascular density gradually decreased as the degree of fibrosis increased and was lower than that of control lungs in the most extensively fibrotic lesions. No vessels were observed inside fibroblastic foci. The potent angiogenic factors vascular endothelial growth factor and interleukin-8 were abundantly produced by capillary endothelial cells and alveolar epithelial cells in highly vascularized alveolar walls. In contrast, venules with CD34-negative but von Willebrand factor-positive endothelial cells localized in the center of the fibrotic lesions were slightly increased and identified as postcapillary venules by three-dimensional reconstructed images. These results indicate the presence of heterogeneous vascular remodeling in usual interstitial pneumonia.

Active chemotherapy for bone metastasis in sarcomatoid renal cell carcinoma.

Sarcomatoid renal cell carcinoma (SRCC) is associated with an aggressive course, high incidence of bone metastasis, and an extremely poor prognosis. There are a few case reports concerning the effectiveness of chemotherapy on metastasis in SRCC. To our knowledge, however, there are no reports describing its effectiveness on bone metastasis. We report a 22-year-old woman with an 8-cm x 7-cm left renal mass. Left nephrectomy was done. The pathological diagnosis was SRCC, INF-beta, pT3aN2. Although, she received continuous infusion of interferon alpha-2a (INFalpha-2a) and interleukin-2 (IL-2) as adjuvant therapy, liver metastasis appeared 2 months later. Resection of the liver metastasis was done. After resection of the metastasis, multiple bone metastases appeared, in both humeri, the left chest wall, the left fourth rib, and the left iliac bone. The patient was treated with gemcitabine, 1000 mg/m(2) (days 1, 8), docetaxel 80 mg/m(2) (day 1), and carboplatin 300 mg/m(2) (day 1). A computed tomography (CT) scan after the first cycle revealed that the multiple osteolytic bone tumors had significantly decreased in size. Her ability of daily life (ADL) improved and this continued for almost 2 months. A second course of chemotherapy, with gemcitabine and IL-2 was given, but it was ineffective, and the patient died approximately 16 months after the initial diagnosis of SRCC. Combination chemotherapy with gemcitabine, docetaxel, and carboplatin was effective for the bone metastasis of SRCC.

Analysis of intrapulmonary vessels and epithelial-endothelial interactions in the human developing lung.

The establishment of a sufficiently wide and functional blood-gas interface is of critical importance in lung development, but development of the intrapulmonary vascular system including alveolar capillary vessels still remains unclear. In this study, we first characterized the structural development of the vascular system in accordance with that of airways in human fetal lungs at the pseudoglandular phase (8, 13, and 16 weeks gestation) by examining the immunohistochemical distribution of CD34 and alpha-smooth muscle actin (SMA). Using double immunohistochemistry and 3-dimensional reconstruction techniques, endothelial cells in the developing lung could be classified into two different types according to the characteristics of their adjacent cells (presence or absence of SMA-positive cells) and their distribution (proximal or distal lung parenchyme). Endothelial cells without SMA-positive cells developed into a capillary network surrounding the budding components of distal airways during the mid-pseudoglandular phase before communicating with proximal vessels. We then examined the immunoreactivity of thrombomodulin and von Willebrand factor (vWF) in endothelial cells. Endothelial cells of the capillary network were mainly positive for vWF during the early gestational stages, but altered their phenotypes to those of mature lungs (vWF negative and thrombomodulin positive) during the terminal sac phase. We subsequently determined the immunohistochemical distribution of vascular endothelial growth factor (VEGF). Epithelial cells of the most distal airways were intensely positive for VEGF. These results suggest that VEGF present in airway epithelial cells is involved in the maturation as well as proliferation of capillary endothelial cells. Epithelial-endothelial interactions during lung development are considered very important in the establishment of the functional blood-gas interface.

[A case of disseminated tuberculosis requiring extended period for the identification of Mycobacterium tuberculosis on culture].

A 80-year-old male visited an outpatient department of a nearby hospital complaining of fever, cough, and poor appetite on June 2000. The patient was diagnosed as bacterial pneumonia and was treated with antibiotics although specific cause could not be identified. After one month, he was hospitalized due to lack of improvement. After admission, acid-fast bacilli (AFB) was found from the bronchial washing. The patient was then transferred to our hospital. Upon admission, sputum smear examination was positive for AFB and MTB was confirmed by PCR. Therapy was initiated with INH 300 mg, RFP 450 mg, EB 1000 mg, and PZA 1000 mg, orally daily. However, on the day following the admission, he became unconscious. Brain MRI showed several small granulomas on the cortex of the bilateral anterior and temporal brain. Although AFB was not detected from the cerebrospinal fluid, tuberculous meningitis was suspected and steroid was given. Nine days after admission, the patient died due to tuberculous meningitis. The isolation of MTB had been attempted on Ogawa culture medium using patient's sputum and liquor, and it took 14 weeks to find colony growth both from sputum and liquor. In the autopsy, numerous granulomas were detected in his lung, liver, kidney, and pancreas. These findings indicate that disseminated growth of MTB occurred in vivo in spite of very slow growth of MTB in vitro.