Immune profile analysis of peripheral blood and tumors of lung cancer patients treated with immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) have become central to lung cancer drug therapy, and establishing biomarkers that can predict effects and adverse events (AEs) is awaited. We prospectively analyzed the association between the immune-related molecular expression in peripheral blood mononuclear cells (PBMCs) and lung cancer tissues, and the effects of ICI monotherapy. Methods: Twenty-one patients with advanced non-small cell lung cancer (NSCLC) who received ICI monotherapy were included. Changes in the expression of immune-related molecules in PBMCs before and after the administration of ICI were analyzed by flow cytometry. The major histocompatibility complex (MHC) class I and programmed cell death-ligand 1 (PD-L1) expression of cancer cells, and the PD-L1, CD8 and CD103 expression of tumor infiltrating immune cells in lung cancer tissue before the administration of ICI were confirmed by immunohistochemistry (IHC). Results: Twenty-one patients were investigated, including 11 adenocarcinoma and 10 squamous cell carcinoma cases. Anti-programmed cell death protein-1 (PD-1) antibody (n=18) and anti-PD-L1 antibody (n=3) were administered. The clinical responses were graded as follows: complete response (CR) (n=1), partial response (PR) (n=7), stable disease (SD) (n=10) and progressive disease (PD) (n=3). Among immune-related molecules expressed in PBMCs, the CD103+ CD39+ CD8+ T cell change after administration closely correlated with the clinical response. In the univariate analyses of the factors associated with progression-free survival (PFS), CD103+ CD39+ CD8+ cell change after administration was identified as a significant prognostic factor, while the CD103+ CD39+ CD8+ cell change after administration and Brinkman index were independent prognostic factors in a multivariate analysis of the factors associated with PFS. Conclusions: The CD103+ CD39+ CD8+ cell change after administration may predict the efficacy of ICIs.

An analysis of the immunological tumor microenvironment of primary tumors and regional lymph nodes in squamous cell lung cancer.

BACKGROUND: Various immune cells that play a central role in antitumor immunity accumulate in primary tumors and regional lymph nodes. Such cellular accumulation and the molecular expression were analyzed to elucidate the immunological tumor microenvironment. METHODS: Fifty squamous cell lung cancer patients with complete resection were included. Resected specimens from primary lung tumors and regional lymph nodes were immunostained for immune-related molecules, such as CD8, CD103, major histocompatibility complex (MHC) class I, and programmed cell death protein ligand-1 (PD-L1), and the relationship between the prognosis and clinicopathological factors was retrospectively analyzed. RESULTS: Tumor-infiltrating lymphocytes and CD8+ lymphocytes, intratumoral and intrastromal CD103+ lymphocytes, tumor diameter, pathological T and N factors, and pathological stage were significant prognostic factors for the disease-specific survival (DSS) in a univariate analysis. In a multivariate analysis, intratumoral and intrastromal CD103+ lymphocytes and pathological T and N factors were independent prognostic factors of the DSS. Significant concordance was found between the PD-L1 expression of primary tumors and metastatic lymph nodes as well as among tumor-infiltrating lymphocytes, CD8+ lymphocytes and CD103+ lymphocytes. Infiltration of CD103+ lymphocytes into the tumor was significantly correlated with an increased PD-L1 expression of cancer cells in both primary tumors and reginal lymph node metastases. Both the intratumoral infiltration of CD103+ lymphocytes and PD-L1 expression of cancer cells were significantly higher in lymph node metastases than in primary tumors. CONCLUSIONS: CD103+ lymphocyte infiltration in the primary tumor was shown to be strongly involved in the prognosis.

Practitioners' identification of informal caregivers' difficulties with activities of daily living interventions for older people with dementia in Japan.

BACKGROUND: Older people with dementia who cannot perform daily activities independently due to cognitive impairment need support at home and in the community. This study identified aspects of activities of daily living (ADL) interventions that advanced dementia care practitioners recognise as challenging for informal caregivers to perform. METHODS: We conducted a self-administered cross-sectional survey on advanced dementia care practitioners, including certified nurses, specialising in gerontological, community health, home care, and visiting nursing, nurses specialising in dementia certified by the Japanese Nursing Association, and dementia care leaders certified by prefectural governors. The participants rated a caregivers' extent of difficulty in aspects of ADL interventions on a four-point Likert scale. Factor analysis was performed to determine ADL intervention aspects that are recognised by advanced dementia care practitioners as challenging for informal caregivers. RESULTS: The highest loaded factors for mild, moderate, and severe cognitive impairment stages were 'right time to draw attention,' 'opportunities to perform ADL,' and 'communicating how to perform ADL without giving up,' respectively. Therefore, it is imperative to educate informal caregivers about the effects of cognitive impairment on ADL performance in people with dementia and enable them to provide concrete ADL interventions and tips to support the persons' autonomy and independence. The Cronbach's alpha values of the highest loaded factors for mild, moderate, and severe cognitive impairment stages were 0.851, 0.925, and 0.946, respectively. Moreover, the cumulative contribution ratios of each stage were 46.04%, 50.52%, and 47.36%, respectively. CONCLUSION: This study dealt with identifying informal caregivers' difficulties with ADL interventions across the stages of dementia. Informal caregivers should be supported on aspects of ADL interventions that are potentially difficult for them to perform. Useful educational content and approaches in training programs for informal caregivers should be developed to enable them to help people with Alzheimer's disease maintain ADL performance toward 'ageing in place' even as the disease progresses.

Validation of the FIGO 2018 staging system of cervical cancer: Retrospective analysis of FIGO 2009 stage IB1 cervical cancer with tumor under 2 cm.

AIM: The International Federation of Gynecology and Obstetrics (FIGO) revised the cervical cancer staging system in 2018. This study aims to validate the revised staging system in patients with tumors <2 cm in size who were classified as FIGO 2009 stage IB1. METHODS: We evaluated 62 women with stage IB1 cervical cancer (FIGO 2009) who underwent radical hysterectomy as the initial treatment between November 2004 and August 2018 in our institution. The patients with FIGO 2009 stage IB1 and tumors <2 cm in size were enrolled. We reclassified their stage according to the FIGO 2018 staging system and analyzed their clinicopathological data retrospectively. RESULTS: Twenty-five patients met the inclusion criteria. According to the FIGO 2018 classification, 9 (36.0%) patients were classified as stage IA, 13 (52.0%) as stage IB1, and 3 (12.0%) as stage IIIC, respectively. One (11.1%), six (46.2%), and three (100%) patients with lymphovascular space invasion were classified as stage IA, IB1, and IIIC, respectively. No significant differences were found in the 5-year overall survival or progression-free survival among the three stages. CONCLUSIONS: As many as 36.0% of patients classified as FIGO 2009 stage IB1 with a tumor <2 cm in size were classified as stage IA in the FIGO 2018 classification. For these cases, a treatment less invasive than radical hysterectomy or radiotherapy might be sufficient. Our results suggest that cervical cancer patients with tumors <2 cm should be carefully diagnosed by performing cervical conization and assessed the pathological findings before hysterectomy.

Relationship between Kita-Kyushu Lung Cancer antigen-1 expression and prognosis of cases with lung squamous cell carcinoma.

BACKGROUND: Previously, we identified the highly immunogenic cancer testicular antigen named Kita-Kyushu Lung Cancer antigen-1 (KK-LC-1). In this study, we analyzed the effect of KK-LC-1 expression on the prognosis of patients with resected squamous cell lung cancer. METHODS: Fifty squamous cell lung cancer patients, who received complete resection, were enrolled in this study. The expressions of KK-LC-1, CD8, human leukocyte antigen (HLA) class I, and programmed cell death protein ligand-1 (PD-L1) were assessed via immunohistochemistry staining using the specimens obtained from the participants. The association between the expression of the abovementioned molecules and patient prognosis was investigated. RESULTS: KK-LC-1 expression was observed in 21 of 50 recruited cases (42%). However, no significant correlation was found between KK-LC-1 expression and patient prognosis. The prognosis was significantly better in lung cancer cases with KK-LC-1 expression in which CD8+ T cells infiltrated the tumor. Regardless of the HLA class I expression or the PD-L1 expression, the KK-LC-1 expression in squamous cell lung cancer could not be detected as a significant prognostic factor. Furthermore, considering the polarity of the cancer tissue as epithelium, staining of KK-LC-1 tended to be strong in the area corresponding to the basal side of the tumor tissue. The Ki-67 expression was frequently observed in cancer cells on the basal side, which was consistent with the KK-LC-1 expression in representative four cases with KK-LC-1-positive squamous cell lung cancer. CONCLUSIONS: Our results indicated that lung squamous cell cancer patients with KK-LC-1 expression and the tumor infiltrating CD8+ T cells might exhibit better prognosis. KK-LC-1 might be highly expressed in cancer cells with high proliferative capacity. Larger cohort analysis is still required for further elucidation and validation of the results of this study.

[A Case of Lung Metastasis of the Breast Cancer with a Remarkable Response to Stereotactic Body Radiation Therapy(SBRT)].

A 69-year-old woman admitted to our hospital with the lump in the left breast. Further examination was performed for the lesion, and it was diagnosed as invasive ductal carcinoma. Partial resection and sentinel lymph node biopsy were performed. Pathological diagnosis was metaplastic carcinoma with squamous metaplasia. As the adjuvant treatment, docetaxel and cyclophosphamide(TC)therapy and radiotherapy was performed. Following the treatment of those, tegafur-uracil was administered for 2 years. Three years after the surgery, an isolated lung metastasis was revealed by CT. Capecitabine and cyclophosphamide(XC)therapy was administered, but not effective. Stereotactic body radiation therapy(SBRT)was performed for the lesion. As a result, the metastatic lesion was obscured. Drug therapy was stopped due to adverse events, and she is observed by no medication. Thirty-six months after SBRT and 78 months after the surgery, the patient is alive without recurrence. SBRT could be an effective treatment strategy for the oligometastais of the lung.

Characteristics of care methods for daily life disabilities in Alzheimer's type dementia that respect autonomy and independence.

AIM: To clarify the characteristics of appropriate care methods for people with daily life disabilities due to Alzheimer's type dementia. DESIGN: A cross-sectional survey study. METHODS: A survey was implemented targeting 2,156 advanced care practitioners for dementia. The postal, self-administered anonymous questionnaire was rated on a 4-point Likert scale to assess the benefits of care for daily life disabilities depending on severity. We conducted factor analysis to determine characteristics of the appropriate care. RESULTS: There were 568 valid responses, a valid response rate of 26.3%. The characteristics found were "Simplicity of necessities" and "Communication using verbal language on what should be done next" for mild cases; "Opportunities for completion of a task are provided with verbal communication," "Marks" and "Arrange the environment with verbal communication" for moderate cases; and "Explain the process in the order of each individual action," "Prevent non-starts and interruptions" and "Confirm intention" for severe cases.

ADAM9 is over-expressed in human ovarian clear cell carcinomas and suppresses cisplatin-induced cell death.

ADAMs (a disintegrin and metalloproteinases) are involved in various biological events such as cell adhesion, migration and invasion, membrane protein shedding and proteolysis. However, there have been no systematic studies on the expression of ADAMs in human ovarian carcinomas. We therefore examined mRNA expression of all the proteolytic ADAM species including ADAM8, 9, 10, 12, 15, 17, 19, 20, 21, 28, 30, 33 and ADAMDEC1 in human ovarian carcinomas, and found that prototype membrane-anchored ADAM9m, but not secreted isoform ADAM9s, is significantly over-expressed in carcinomas than in control non-neoplastic ovarian tissue. Among the histological subtypes of serous, endometrioid, mucinous and clear cell carcinomas, ADAM9m expression was highest in clear cell carcinomas. Immunohistochemistry showed that all the clear cell carcinoma samples displayed ADAM9m primarily on the carcinoma cell membrane. By immunoblotting, ADAM9m was detected mainly in an active form in the clear cell carcinoma tissues. When two clear cell carcinoma cell lines (RMG-I and TOV21G cells) with ADAM9m expression were treated with cisplatin, viability was significantly reduced and apoptosis increased in ADAM9m knockdown cells compared with mock transfectants. In addition, treatment of the cells with neutralizing anti-ADAM9m antibody significantly decreased viability compared with non-immune IgG, whereas ADAM9m over-expression significantly increased viability compared with mock transfectants. Our data show, to the best of our knowledge, for the first time, that ADAM9m is over-expressed in an activated form in human ovarian clear cell carcinomas, and suggest that ADAM9m plays a key role in cisplatin resistance.

Late-onset congenital lateral dermal sinus tract.

Cases of laterally located, congenital dermal sinus tracts are extremely rare, with only six having been reported to date. We describe a case of a 14-year-old girl who developed symptoms of this type of sinus tract at an age that was considerably older than is usually reported. At the age of 12 years, the patient exhibited a purulent discharge from a pit on the right buttock. MRI indicated the presence of two tracts running from the right buttock skin to a cystic lesion that had formed on the right ala of the sacral spine. The lesion was surgically resected and successfully reconstructed using a partial iliocostalis lumborum muscle flap, without any functional morbidity. From our experience, such flaps appear to be appropriate treatment choices for lateral congenital dermal sinus tracts that develop late and result in large defects.

A case of an infant suffered from a fatal scald injury - validity and limitations of postmortem CT imaging.

A 9months-old infant has died of scald burn by the hot water from the fallen electric pot at home. Postmortem computed tomography (CT) scanning prior to autopsy contributed to exclude the possibilities of old and new bone fractures or hidden massive hemorrhages. This procedure helped the pathologists to avoid dissecting all the extremities, which is time-consuming, laborious and often hurtful to the innocent parents of the deceased. On the other hand it did not successfully show the distribution of the scald burn injury on the skin, which reminded us of the importance of external examination even when the whole-body CT is performed. The manner of death was considered to be accident since the cause of death was burn shock and there was no significant evidence suggesting child abuse. Scene investigation and reproductive experiment have revealed that there was a structural problem in the lid of the pot, which comes off very easily in a certain condition. In order to prevent a similar accident, report of the case to the manufacturer is essential for the improvement of the apparatus. This case, however, has been remained to be unreported because of the confidentiality of the investigative information in judicial autopsy. Finally, we recommend a partial revision of the reporting system in Japan to prevent the recurrence of such tragic accidents.

Obscure gastrointestinal bleeding: resection of a pyogenic granuloma of the ileum via double-balloon enteroscopy.

Pyogenic granulomas usually occur on the skin or oral mucosa; however, they rarely develop in the gastrointestinal tract, particularly in the ileum. We report the case of an 82-year-old female who experienced occasional bloody stools. Initially, no significant bleeding source could be identified via conventional endoscopy; however, repeat capsule endoscopy identified a bleeding polyp (8 mm) in the ileum. Therefore, we resected the polyp via double-balloon enteroscopy. Histopathological findings showed increased, lobulated, and enlarged capillaries and desquamated epithelium indicative of epithelial erosion. In addition, neutrophil-predominant inflammatory cell infiltrate and interstitial edema were observed in the intercapillary stroma. Immunohistochemical analysis showed positive staining for vascular endothelial cell markers. Previous reports have mentioned that pyogenic granulomas in the oral cavity were associated with the female hormonal receptor, vascular endothelial growth factor, and proliferative immune markers; however, no significant staining was observed in our patient. This is the first report discussing an association between pyogenic granulomas and these markers. Pyogenic granulomas in the ileum are rare and may cause fatal anemia. Pyogenic granulomas should be considered in the differential diagnosis of obscure gastrointestinal bleeding.

Src plays a key role in ADAM28 expression in v-src-transformed epithelial cells and human carcinoma cells.

ADAM28, a disintegrin and metalloproteinase 28, is overexpressed by carcinoma cells with direct correlations with carcinoma cell proliferation and progression in human lung and breast carcinomas. However, the molecular mechanisms of ADAM28 gene expression in carcinoma cells remain elusive. Herein, we investigated the expression of ADAM28 in Madin-Darby canine kidney epithelial cells transformed by oncogenes, including v-src, LMP1, ErbB2, Ha-Ras, and c-Fos, and found that v-src transformants selectively induce ADAM28. Implantation of the v-src transformants showed a progressively growing tumor, which was significantly suppressed by local injections of anti-ADAM28 antibody. ADAM28 expression in v-src transformants was partially inhibited by treatment with inhibitors to Src kinase, mitogen-activated protein kinase kinase (MEK), phosphatidylinositol 3-kinase (PI3K), or mammalian target of rapamycin, and abrogated by v-Src kinase inhibitor, radicicol, or a mixture of MEK and PI3K inhibitors. Human carcinoma cell lines of the lung, breast, ovary, kidney, and colon showed ADAM28 expression, which was correlated with phosphorylation of c-Src and suppressed by the inhibitors in a similar way to v-src transformants. IHC of the human tumor tissues demonstrated co-expression of ADAM28 and phosphorylated Src in neoplastic cells of the breast, lung, and colon carcinomas and some adenomas of the colon, but not in nonneoplastic colon mucosa. Our data provide, to the best of our knowledge, the first evidence that Src is an inducer of ADAM28 gene expression through the MEK/extracellular signal-regulated kinase and PI3K/mammalian target of rapamycin pathways.

Hemorrhagic onset of cerebellar pilocytic astrocytoma in an adult: a case report and review of the literature implying a possible relation of degenerative vascular changes to the massive intratumoral hemorrhage.

Pilocytic astrocytoma (PA) is a low-grade astrocytic tumor arising predominantly during the first two decades of life. Hemorrhagic onset of PAs is uncommon, and the etiology of hemorrhage remains unclear. Here we report a case of hemorrhagic onset of cerebellar PA in a 29-year-old man who presented with a week-long history of headache and gait instability. Computed tomography and magnetic resonance imaging revealed a hemorrhagic tumor located in the right cerebellar hemisphere, and total resection was performed. Histological examination showed bipolar glial cell proliferation in a biphasic pattern in a compact area and a loose microcystic area with Rosenthal fibers and eosinophilic granular bodies, indicating PA. Prominent changes in tumor vasculature, including aggregation of sclerotic thick-walled and ectatic thin-walled vessels, was observed, and nodules of thrombi containing complex vascular proliferation suggesting recanalized thrombi formed in partially ruptured vessels were also found. Thus, rupture of these abnormal vessels appeared to be the cause of hemorrhage. Review of the literature revealed that age distribution of patients with hemorrhagic PAs tends to be older than that of patients with general PAs. These findings imply a possibility that degenerative changes in blood vessels in long-standing PAs might be related to the mechanisms of spontaneous intratumoral hemorrhage.

Home care nurses' provision of support to families of the elderly at the end of life.

In this article we describe our study of assistance for family decisions and caregiving by Japanese home care nurses to families of elderly relatives at the end of life. The participants were 31 nurses who had been evaluated as providing good end-of-life care. We carried out semistructured interviews concerning the practice of family support in two cases (cancer and noncancer). We conducted a qualitative analysis using the constant comparative approach and derived several categories inductively. Home care nurses are responsible for (a) estimating the possibility of dying at home, (b) visualizing what is coming and what can be done, (c) proposing where and how the family can say goodbye, (d) building family consensus, (e) coordinating resources, and (f) offering psychological support for end-of-life care. End-of-life family care by home care nurses is a process in which multiple components of care are provided with changing content as death approaches.

Absent inner dynein arms in a fetus with familial hydrocephalus-situs abnormality.

We report a family in which a healthy, unrelated couple had a male fetus with bilateral ventriculomegaly, a normal liveborn girl, a hydatidiform molar pregnancy, a female fetus with ventriculomegaly and situs abnormalities, and a male fetus with hydrocephalus, a three-lobed left lung, and defective tracheal cilia with absent inner dynein arms and a single centriole. A mutation analysis of FOXJ1 and POLL in the last fetus with ciliary defect revealed no mutation within their coding regions. The presence of three affected fetuses of both sexes in a family with phenotypically normal parents suggests that the condition was inherited as an autosomal recessive trait. A thorough evaluation of the thoracic and abdominal situs is recommended before counseling a family of a child with hydrocephalus, because the recognition of situs defects may point to the diagnosis of primary ciliary defect and recurrence risk of 25% for siblings. This figure is much higher than the general risk of 1-2% for siblings of a patient with isolated hydrocephalus.