Androgens Alleviate Allergic Airway Inflammation by Suppressing Cytokine Production in Th2 Cells.

Asthma is more common in females than males after adolescence. However, the mechanism of the sex bias in the prevalence of asthma remains unknown. To test whether sex steroid hormones have some roles in T cells during development of asthma, we analyzed airway inflammation in T cell-specific androgen receptor (AR)- and estrogen receptor (ER)-deficient mice. T cell-specific AR-deficient male mice developed severer house dust mite-induced allergic airway inflammation than did control male mice, whereas T cell-specific ERα- and ERß-deficient female mice exhibited a similar degree of inflammation as for control female mice. Furthermore, administration of dihydrotestosterone reduced cytokine production of Th2 cells from control, but not AR-deficient, naive T cells. Transfer of OT-II transgenic AR-deficient Th2 cells into wild-type mice induced severer allergic airway inflammation by OVA than transfer of control Th2 cells. Gene expression profiling suggested that the expression of genes related with cell cycle and Th2 differentiation was elevated in AR-deficient Th2 cells, whereas expression of dual specificity phosphatase (DUSP)-2, a negative regulator of p38, was downregulated. In addition, a chromatin immunoprecipitation assay suggested that AR bound to an AR motif in the 5' untranslated region of the Dusp2 gene in Th2 cells. Furthermore, the Dusp2 promoter with a wild-type AR motif, but not a mutated motif, was transactivated by dihydrotestosterone in a reporter assay. Finally, forced expression of DUSP-2 by retrovirus vector reduced IL-4 expression in Th2 cells. Thus, these results suggest that androgen signaling suppresses cytokine production of Th2 cells by inducing DUSP-2, explaining, in part, the sex bias of asthma after adolescence.

Clinical outcomes of sentinel node navigation surgery in patients with preoperatively estimated stage IA endometrial cancer and evaluation of validity for continuing sentinel node navigation surgery based on dispersion of recurrence probability.

BACKGROUND: To evaluate the feasibility of the use and continuation of sentinel lymph node navigation surgery (SNNS) as an alternative to pelvic lymph node dissection (PLND) for patients with preoperatively estimated stage IA endometrial cancer. METHODS: This retrospective study selected the electronic medical records of all patients who had received CT scans and MRI imaging before surgery from April 1, 2009 to March 31, 2021. Sentinel lymph nodes (SLNs) were detected by administrating 99mTc-phytate and/or indocyanine green into the cervix, and the clinical outcomes of the patients who underwent SNNS or PLND were evaluated. Furthermore, in case of nodal recurrence, a new procedure to determine whether the facility should continue with SNNS or not was developed that compares the maximum likelihood hypothesis and an alternative one based on recurrence rates. RESULTS: Among 137 patients, SLN biopsies with ultrastaging were performed on 91 patients. The SLN detection rate was 95.6%. Over a 59-month median observation period, no statistically significant differences were shown in overall survival, disease-specific survival and disease-free survival between the SNNS and PLND groups when introducing the propensity score method (p-values: 0.06, 0.153, and 0.625, respectively). Our procedure demonstrated that, in our department without recurrence up to the 65th attempt, it was possible to continue SNNS if a recurrence occurs at the 66th attempt. CONCLUSION: This study suggests the validity of SNNS as an alternative to PLND. Even in the absence of evidence from randomized controlled trials, we can confirm the validity of continuing SNNS using our procedure.

Detection of MEAF6-PHF1 translocation in an endometrial stromal nodule.

Endometrial stromal nodule (ESN) and low-grade endometrial stromal sarcoma (LG-ESS) are rare uterine tumors known as endometrial stromal tumors (ESTs). In addition to their similarity in morphological features, recent studies have shown that these two tumors share common genetic alterations. In particular, JAZF1-SUZ12 fusion is found with high frequency in both ESN and LG-ESS. In LG-ESS, some minor fusions have also been described, which include rearrangements involving PHF1 and its partner genes, such as JAZF1, EPC1, MEAF6, BRD8, EPC2, and MBTD1. Because of the rarity of ESN, genetic alterations other than JAZF1 fusion have not been investigated in detail. In this study, we performed a next-generation sequencing-based analysis in a case of ESN with peripheral metaplastic bone formation and detected MEAF6-PHF1 fusion, which has been reported in a small subset of uterine LG-ESSs and soft tissue ossifying fibromyxoid tumors. The finding that MEAF6-PHF1 fusion is a background genetic abnormality detected both in ESN and LG-ESS, along with JAZF1-SUZ12, provides further support for the similarity and continuum between these two types of ESTs. Furthermore, the association between metaplastic bone formation and MEAF6-PHF1 fusion may not be limited to soft tissue tumors.

Invasive Micropapillary Carcinoma of the Uterine Cervix: Case Report of a Rare Entity.

Invasive micropapillary carcinoma (IMPC) is a rare subtype of adenocarcinoma found in many organs. Only 1 case of IMPC of the uterine cervix has been reported. We report a rare case of IMPC in the uterine cervix. A 61-yr-old woman presented to our hospital for vaginal bleeding and abdominal pain. A papillary tumor was found in the uterine cervix. Cervical cytology revealed abnormal cells suggesting carcinoma in situ and adenocarcinoma. A follow up biopsy revealed adenocarcinoma. She underwent radical hysterectomy and bilateral adnexectomy. Histologically, carcinoma in situ and IMPC were found in the uterine cervix. Lymphatic infiltration was present in the cerix and in the right cardinal ligament. A pelvic lymph node metastasis was also identified. Clinical FIGO stage was IIb and pathologic stage was pT2bN1M0. Postoperative positron emission tomography-computed tomography revealed paraaortic lymph node metastasis. She is alive with disease 2 yr 9 mo after surgery. Positive p16 immunostaining and high-risk human papilloma virus in situ hybridization revealed human papilloma virus infection. Interleukin-17 was expressed in the tumor cells which might be related to the extensive neutrophilic infiltration and tumor progression. This is the first case report in which interleukin-17 expression is observed in the tumor cells of IMPC.

Oxidative stress responses in human bronchial epithelial cells exposed to cigarette smoke and vapor from tobacco- and nicotine-containing products.

The use of novel tobacco- and nicotine-containing vapor products that do not combust tobacco leaves is on the rise worldwide. The emissions of these products typically contain lower numbers and levels of potentially harmful chemicals compared with conventional cigarette smoke. These vapor products may therefore elicit fewer adverse biological effects. We compared the effects of emissions from different types of such products, i.e., our proprietary novel tobacco vapor product (NTV), a commercially available heat-not-burn tobacco product (HnB), and e-cigarette (E-CIG), and a combustible cigarette in a human bronchial epithelial cell line. The aqueous extract (AqE) of the test product was prepared by bubbling the produced aerosol into medium. Cells were exposed to the AqEs of test products, and then glutathione oxidation, Nrf2 activation, and secretion of IL-8 and GM-CSF were examined. We found that all endpoints were similarly perturbed by exposure to each AqE, but the effective dose ranges were different between cigarette smoke and the tobacco- and nicotine-containing vapors. These results demonstrate that the employed assays detect differences between product exposures, and thus may be useful to understand the relative potential biological effects of tobacco- and nicotine-containing products.

Hyperphosphatasemia in leiomyosarcoma of the uterus: Two case reports and a literature review.

Some tumors are known to produce alkaline phosphatase (ALP). Seven cases of uterine leiomyosarcoma were identified from the clinical records of Sakai City Medical Center from January 2006 to December 2014. Patients' ages ranged from 47 to 75 years (median: 58). Clinical stages were IB, IIB, IIIA, and IVB in four, one, one, and one cases, respectively. Of these, two were found to have hyperphosphatasemia before surgery, and the elevated ALP level decreased after surgery, and increased with disease recurrence. In the cases of hyperphosphatasemia, leiomyosarcoma cells showed positive staining for ALP. There was no correlation between serum ALP and lactate dehydrogenase, or ALP and cancer antigen 125. The combination of ALP, lactate dehydrogenase, and cancer antigen 125 may be more useful for diagnosis and follow-up of leiomyosarcoma.

[A Case of Epithelioid Angiomyolipoma of the Kidney with Tumor Thrombus Extending into the Renal Vein : Case Report].

A 31-year-old man was referred to our hospital for macroscopic hematuria. An abdominal computed tomography (CT) scan showed a 36×30 mm enhancing left renal tumor with tumor thrombus extending into the left renal vein. Therefore,we diagnosed the tumor as a clinically classified cT3aN0M0 left renal cell carcinoma. Retroperitoneal laparoscopic radical left nephrectomy with renal vein thrombectomy was performed,with removal of the left kidney with the mass and tumor thrombus en bloc. The pathological diagnosis was epithelioid angiomyolipoma (EAML) of the left kidney. EAML is a rare tumor with malignant potential. In this case,although no signs of recurrence or metastasis have been observed for 9 months post-operation,we recommended a careful follow-up regimen.

[A Case of Arteriovenous Malformation Located in Retroperitoneum].

A 67-year-old woman was referred to our hospital for precise examination and treatment as an abdominal computed tomographic (CT) scan showed a retroperitoneal tumor located below the hilus of the right kidney. The enhanced CT and magnetic resonance imaging (MRI) revealed contrast enhancement in both early and late phase, which confirmed that the tumor showed abundant blood perfusion and adhered to the duodenum. We performed open surgery in order to remove the tumor and make a precise diagnosis. The tumor was excised en bloc with a part of the gonadal vein because the right gonadal vein was adjacent to the tumor in the craniocaudal direction. The pathological diagnosis was arteriovenous malformation. Arteriovenous malformation located in the retroperitoneum is very rare.

[Metastasis to the Tongue from Renal Cell Carcinoma 10 Years after Nephrectomy : A Case Report].

A 71-year-old woman underwent left radical nephrectomy for renal cell carcinoma (clear cell carcinoma, pT1bN0M0) ten years previously. She noticed a tumor on the tip of her tongue and was admitted for dental and oral surgery. The tumor was about 10 mm in size, and tumor resection was done. It was pathologically diagnosed as clear cell carcinoma, which was metastasis of renal cell carcinoma. Computer tomography scan during the same period revealed left hilar lymph node and bilateral lung metastases. We chose to use sunitinib as the treatment for the metastases. Computer tomography revealed a complete response (CR) after sunitinib treatment was given for 10 months, and we are still continuing the treatment to maintain the CR status.

[Damage Control Surgery for Perforation of Colon Cancer].

Perforation due to colon cancer maycause peritonitis and septic shock. In these cases, we maynot be able to rescue the patients in spite of emergencysurgical intervention; in these conditions, owing to limitations of operation time, it is difficult for us to assess the state or extent of the disease and to perform an ideal oncological surgerywith dissection of lymph nodes. To overcome these limitations, we introduce the concept of "damage control surgery" developed in the trauma region to treat perforations of colon cancer. There are 3 steps: first, the perforated intestine is resected and the peritoneal cavityis lavaged to control contamination. Open abdominal management is used as a temporaryabdominal closure; second, sepsis is treated in the ICU; and third, based on the treatment strategydecided upon after consulting a colorectal surgeon and the patient's family, a colostomy, anastomosis, and extra dissection of lymph node are performed before abdominal closure. We report the fatal case of a 92-year-old woman who had developed severe shock to indicate the significance of this strategy.

Incidence of serous tubal intraepithelial carcinoma (STIC) by algorithm classification in serous ovarian tumor associated with PAX8 expression in tubal epithelia: a study of single institution in Japan.

Serous ovarian carcinoma is now hypothesized to originate from fallopian tube epithelium (FTE). We investigated the FTE abnormalities in the patients with epithelial ovarian tumors. Our study included 55 cases of serous tumors (24 carcinomas, 8 borderline tumors, and 23 adenomas), 14 mucinous carcinomas, 22 endometrioid carcinomas, 5 clear cell carcinomas, and 2 malignant Brenner tumors. FTE was diagnosed by the diagnostic algorithm, which combines the data of morphology, and p53, Ki-67 immunostaining, as serous tubal intraepithelial carcinoma, serous tubal intraepithelial lesion, p53 signature, and normal/reactive. Serous tubal intraepithelial carcinoma, serous tubal intraepithelial lesion, p53 signature, and normal/reactive were observed in 5, 3, 0, and 16 cases in serous carcinoma; 0, 3, 0, and 5 cases in serous borderline tumor; 0, 1, 1, and 21 cases in serous adenoma; 0, 0, 1, and 13 cases in mucinous carcinoma; 0, 0, 3, and 19 cases in endometrioid carcinoma; 0, 0, 0, and 5 cases in clear cell carcinoma; and 0, 1, 0, and 1 case in malignant Brenner tumor. Among tumors of serous histology and between carcinomas, FTE abnormalities differed significantly (P<0.05). Serous tubal intraepithelial carcinomas were only found in serous carcinoma. The incidence of secretory cell proliferation (SCP) was examined by PAX8 expression. The rate of SCP was extremely high in serous carcinoma (96%). Among tumors of serous histology and between carcinomas, an incidence of SCP differed significantly (P<0.05). Patients with SCP were significantly older (P<0.0001). Our observations were concordant with the hypothesis of serous ovarian carcinogenesis. The SCP has a meaningful association with serous ovarian cancer.

[A Case of Bone Metastasis from Early Gastric Cancer after a Five-Year Disease-Free Interval Following Gastrectomy].

A woman in her 50s underwent distal gastrectomy and D1+b dissection in December 2005 for early gastric cancer that was diagnosed as a signet-ring-cell carcinoma, fStage Ⅱ (T1a, N2, H0, P0, CY0, M0) with 12 lymph node metastases in the second field. Multiple bone metastases were diagnosed on the basis of CT and bone scintigraphy findings and serum ALP elevation (2,743 IU/L) I n December 2010. Fourteen courses of S-1 plus CDDP and 4 mg of zoledronate were administered from January to September in 2011. Pancytopenia, D-dimmer elevation, myelocytes, and metamyelocytes were observed in October 2012, indicating she had bone marrow metastasis. She was treated with a transfusion, anti-DIC therapy, and paclitaxel. She died from gastric cancer in December 2012. We report a rare case of recurrence with bone metastasis from early gastric cancer. S-1 plus CDDP chemotherapy and zoledronate therapy is an effective treatments for multiple bone metastases from gastric cancer.

[A Case of Invasive Ductal Carcinoma in the Fat Replacement of the Pancreatic Body and Tail].

A 56 year-old woman with obesity (BMI3 2) and diabetes mellitus was diagnosed with right renal cell carcinoma. She underwent right nephrectomy 1 year ago. Seven months after surgery, CT revealed a rapidly growing mass near the spleen. The mass showed slight accumulation of FDG (SUVmax=2.4) on PET-CT. Since the lesion grew rapidly and was not enhanced in the early phase of enhanced CT, we diagnosed pancreatic cancer. Distal pancreatectomy and splenectomy were performed. The final pathological diagnosis was invasive ductal carcinoma in the fat replacement of the pancreatic body and tail. Postoperatively, the patient had no complications such as pancreatic fistula or aggravation of glucose intolerance. She received postoperative chemotherapy with gemcitabine. Since she developed pulmonary artery thrombosis, postoperative chemotherapy was interrupted after 8 courses. Thirty-two months after the surgery, she was still living without any recurrence. Acinar cells were absent in the fat replacement of the pancreas, but the pancreatic duct cells were still present. There was carcinoma in situ in the main pancreatic duct surrounding chronic inflammation. Fat replacement itself could be potentially precursor of the pancreatic cancer.

Evaluation of endometrial cytology prepared with the Becton Dickinson SurePath™ method: a pilot study by the Osaki Study Group.

OBJECTIVE: To evaluate the sensitivity and specificity of the BD SurePath™ liquid-based Papanicolaou test for assessing the cytology of intrauterine endometrial samples according to newly devised cytological diagnostic criteria and a novel descriptive reporting format. MATERIALS AND METHODS: One hundred and twenty-two endometrial samples were analyzed. All samples were obtained directly from the intrauterine cavity using the Uterobrush or Honest Super Brush. The samples used for the histological examination and cytological tests were collected simultaneously. Our study group devised new cytological diagnostic criteria for examining endometrial samples: the Osaki Study Group method. In this study, histological diagnosis was considered to be the gold standard for cytological diagnosis. A novel descriptive reporting format was also used. RESULTS: Satisfactory cytological specimens were obtained in all cases. The sensitivity and specificity of the SurePath endometrial cytological examination method were 96.4 and 100%, respectively. CONCLUSION: These results indicate that the SurePath method is acceptable for clinical use. Since the SurePath method seems to be easier and allows greater preparation standardization than the conventional method, coupling it with our newly devised cytological diagnostic criteria and descriptive reporting format might represent a reliable diagnostic method for assessing endometrial specimens.

[Long-term survival of a patient with esophageal metastasis from breast cancer treated with esophagectomy].

Esophageal metastasis from breast cancer is rarely observed. We encountered a case of long-term survival after esophageal metastasis from breast cancer that was treated with esophagectomy. A 79-year-old woman developed dysphagia 26 years after radical mastectomy. Endoscopic examination revealed stenosis at the mid-thoracic esophagus. An esophageal biopsy led to a diagnosis of undifferentiated cancer. A computed tomography (CT) scan revealed a massive tumor in the esophagus, but no distant metastases. Esophagectomy was performed with the suspicion of primary or metastatic esophageal cancer. Histopathologically, the excised tumor was an adenocarcinoma, which had histopathological features similar to that of the breast cancer. Accordingly, the adenocarcinoma was diagnosed as esophageal metastasis of the breast cancer. The patient is still alive 8 years after the esophagectomy.

[A case of curative surgery for HER2-positive gastric cancer after chemotherapy using paclitaxel combined with trastuzumab].

A 74-year-old man was diagnosed with unresectable HER2-positive gastric cancer due to metastases to distant lymph nodes. Paclitaxel combined with trastuzumab was administered as third-line chemotherapy. After 4 courses of therapy, the metastases to distant lymph nodes disappeared with no evidence of progressive disease. Downstaging by chemotherapy made curative treatment feasible and he underwent distal gastrectomy. The patient has been free from recurrent disease 13 months after surgery.

[Long-term efficacy of chemotherapy for unresectable gastric cancer with multiple bone metastases-a case report].

A 49-year-old man was admitted to our hospital with back pain, appetite loss, and body weight loss in January 2009. Gastroduodenal endoscopy, abdominal computed tomography( CT), and magnetic resonance imaging( MRI) revealed type 4 advanced gastric cancer( signet-ring cell carcinoma) with multiple lymph node( No. 16 LNs), right adrenal gland, and multiple bone metastases. Between February 2009 and April 2011, 20 courses of S-1( 80 mg/m2) plus CDDP( 60 mg/m2) and zoledronic acid hydrate (4 mg/body) were administrated. Since May 2011, S-1 (70 mg/m2) and zoledronic acid hydrate( 4 mg/body) have been continued. The lymph node and adrenal gland metastases showed a complete response( CR), and the gastric tumor showed a partial response; however, the bone metastases did not show CR or progressive disease (PD) for 4 years after initiation of therapy. Chemotherapy with zoledronic acid hydrate is considered as a useful therapeutic option for advanced unresectable gastric cancer with multiple bone metastases.

Tumor-Infiltrating CD8-Positive T-Cells Associated with MMR and p53 Protein Expression Can Stratify Endometrial Carcinoma for Prognosis.

BACKGROUND: Inspired by the molecular classification of endometrial carcinoma (EC) proposed by The Cancer Genome Atlas Research Network (TCGA), we investigated tumor-infiltrating CD8-positive T-cell as well as DNA mismatch repair (MMR) protein and p53 protein expression, and we developed a new classification system for ECs to predict patients' prognosis using immunohistochemical methods. METHODS: The study included 128 patients with ECs who underwent surgery. Paraffin-embedded tissue sections of the tumor were stained using antibodies against MMR protein, p53, and CD8. Cases were stratified into four classes by a sequential algorithm. An immunohistochemical classification system for ECs (ICEC) was created, including HCD8, MMR-D, LCD8, and p53 LCD8. RESULTS: In ICEC, 16 cases (12.5%), 27 cases (21.09%), 67 cases (52.34%), and 18 cases (14.06%) belonged to HCD8, MMR-D, LCD8, and p53 LCD8, respectively. ICEC did not show any correlation with clinical stage, lymphovascular space invasion, or lymph node metastasis. However, the p53 LCD8 class contained a significantly higher proportion of G3 ECs and serous carcinoma (p < 0.0001). ICEC showed prognostic significance in overall survival (OS) (p < 0.0001) and disease-free survival (DFS) (p < 0.0001). The class of p53 LCD8 showed the worst prognosis among the classes. CONCLUSIONS: ICEC classification is useful in predicting the prognosis of ECs.

Autoimmune Pulmonary Alveolar Proteinosis during the Treatment of Idiopathic Inflammatory Myopathy.

Approximately 50% of idiopathic inflammatory myopathies (IIMs) are associated with interstitial lung disease (ILD). Typically, IIM-ILD manifests as nonspecific interstitial pneumonia. We herein report a rare case of a 78-year-old man with autoimmune pulmonary alveolar proteinosis (PAP) that developed during IIM treatment. The diagnosis of autoimmune PAP was based on detecting anti-granulocyte-macrophage colony-stimulating factor antibodies. We postulated that PAP may have been induced by IIM treatment with prednisolone. Our case suggests that the possibility of autoimmune PAP should be considered in patients with lung lesions during the clinical course of IIM.

Development of a micronucleus test using the EpiAirway™ organotypic human airway model.

BACKGROUND: The use of organotypic human tissue models in genotoxicity has increased as an alternative to animal testing. Genotoxicity is generally examined using a battery of in vitro assays such as Ames and micronucleus (MN) tests that cover gene mutations and structural and numerical chromosome aberrations. At the 7th International Workshop on Genotoxicity Testing, working group members agreed that the skin models have reached an advanced stage of maturity, while further efforts in liver and airway models are needed [Pfuhler et al., Mutat. Res. 850-851 (2020) 503135]. Organotypic human airway model is composed of fully differentiated and functional respiratory epithelium. However, because cell proliferation in organotypic airway models is thought to be less active, assessing their MN-inducing potential is an issue, even in the cytokinesis-blocking approach using cytochalasin B (CB) [Wang et al., Environ. Mol. Mutagen. 62 (2021) 306-318]. Here, we developed a MN test using EpiAirway™ in which epidermal growth factor (EGF) was included as a stimulant of cell division. RESULTS: By incubating EpiAirway™ tissue with medium containing various concentrations of CB, we found that the percentage of binucleated cells (%BNCs) almost plateaued at 3 µg/mL CB for 72 h incubation. Additionally, we confirmed that EGF stimulation with CB incubation produced an additional increase in %BNCs with a peak at 5 ng/mL EGF. Transepithelial electrical resistance measurement and tissue histology revealed that CB incubation caused the reduced barrier integrity and cyst formation in EpiAirway™. Adenylate kinase assay confirmed that the cytotoxicity increased with each day of culture in the CB incubation period with EGF stimulation. These results indicated that chemical treatment should be conducted prior to CB incubation. Under these experimental conditions, it was confirmed that the frequency of micronucleated cells was dose-dependently increased by apical applications of two clastogens, mitomycin C and methyl methanesulfonate, and an aneugen, colchicine, at the subcytotoxic concentrations assessed in %BNCs. CONCLUSIONS: Well-studied genotoxicants demonstrated capability in an organotypic human airway model as a MN test system. For further utilization, investigations of aerosol exposure, repeating exposure protocol, and metabolic activation are required.